British Medical Bulletin

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British Medical Bulletin 58:109-127 (2001)
© 2001 The British Council

HIV-1 transmission and acute HIV-1 infection

Pokrath Hansasuta and Sarah L Rowland-Jones

Human Immunology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK

	Abstract

Top Abstract HIV-1 transmission Factors influencing... Early events in primary... Clinical presentation of primary... Immunopathological events in... Treatment of primary HIV-1... Key points for clinical... Acknowledgements References

 
An understanding of the central events in the transmission of HIV-1 infection is critical to the development of effective strategies to prevent infection. Although the main routes of transmission have been known for some time, surprisingly little is known about the factors that influence the likelihood of transmitting or acquiring HIV-1 infection. Once infection has taken place, the series of virological and immunopathological events that constitute primary HIV-1 infection are thought to be closely linked with the subsequent clinical course of the infected person. Recent studies have provided some support for the notion that intervention with aggressive anti-retroviral drug therapy at this stage has the potential to prevent some of the damage to the immune system that will otherwise develop in the vast majority of infected people.

	HIV-1 transmission

Top Abstract HIV-1 transmission Factors influencing... Early events in primary... Clinical presentation of primary... Immunopathological events in... Treatment of primary HIV-1... Key points for clinical... Acknowledgements References

 
Routes of HIV-1 transmission

The main routes of HIV-1 transmission are well-known, and are listed in Table 1. On a world-wide scale, the vast majority of new infections are acquired through heterosexual contact. The likelihood of transmission from male to female has been estimated to be as high as 8-fold more likely that from female to male¹, although the biological basis for this is not fully understood. Transmission of HIV-1 through oro-genital contact, although rare, is an increasingly recognised route of infection (reviewed by Caceres and van Griensven²).

View this table: [in this window] [in a new window]   Table 1 Routes and likelihood of HIV-1 transmission

 
In non-industrialised countries, as many as 42% of the children born to infected mothers will become infected³, either at birth or in the postnatal period through exposure to infected breast-milk (reviewed by Nduati⁴). In contrast, vertical transmission of HIV-1 infection is now becoming a rare event in industrialised countries, through a combination of anti-retroviral therapy, obstetric management and the use of alternative infant feeding methods. The high rates of breast-milk transmission to infants of infected mothers emphasise the potential for HIV-1 to establish infection through the oral route. This is further demonstrated by the relative ease in which infant macaques can become infected with SIV through the atraumatic application of virus to the back of the tongue⁵. Pathological studies in macaques infected by this route show that the infection begins locally in the tonsils, from where it spreads rapidly to other lymphoid tissue⁶.

There is little evidence for HIV-1 being transmitted between household contacts in the absence of a recognised route of transmission (reviewed by Gershon et al⁷), although occasional cases have been reported^8,9.

Most countries have implemented screening procedures for donated blood that substantially reduce the risk of blood-borne infection¹⁰10. Where the screening is limited to antibody testing, there is a small risk of using blood from a donor in the ‘window’ period of acute HIV infection, before antibodies have developed.

The chances of HIV-1 infection in healthcare workers after accidental exposure to contaminated blood is generally very low¹¹, and no cases have so far been reported in subjects given combination anti-retroviral therapy post-exposure prophylaxis.

What influences the ‘infectivity’ of the infected person?

The key factor influencing a person's likelihood of transmitting HIV-1 infection appears to be their viral burden – this can be predicted by measuring plasma viral load. A recent study in Rakai, Uganda³³ showed that transmission was rare from people with viral loads of less than 1500 RNA copies/ml. It is likely that genital viral secretion (which is harder to measure) is more relevant to infectivity than plasma viraemia³⁴: genital shedding of virus is not always predicted by plasma viral load, and is increased during genital infection and in people with severe vitamin A deficiency³⁵. It is becoming clear that HIV can be transmitted by people with apparently good viral suppression on anti-retroviral therapy: for example, when virus persists in relevant body compartments such as semen³⁶.

Host genetic factors can influence the infectiousness of the contact: it has recently been shown in a cohort of Kenyan HIV-infected women that those with one copy of a mutant allele of the gene encoding the chemokine SDF-1 (which binds to the co-receptor, CXCR4, often used by HIV in late infection) were more likely to transmit the infection to their infants³⁷. It is feasible that certain HIV-1 strains are more infectious than others, but this has not been unequivocally demonstrated in vivo (reviewed by Vernazza et al³⁸). The E clade strain of HIV, which rapidly outstripped B clade HIV-1 as the major strain in the Thai epidemic, was initially thought to infect Langerhans' cells more readily³⁹, but this finding could not be reproduced by others⁴⁰. However, it is well-documented that HIV-2 is much less efficiently transmitted by the sexual route than HIV-1 and is hardly ever transmitted from mother to child (reviewed by Whittle et al⁴¹).

	Factors influencing susceptibility and resistance to HIV-1 infection

Top Abstract HIV-1 transmission Factors influencing... Early events in primary... Clinical presentation of primary... Immunopathological events in... Treatment of primary HIV-1... Key points for clinical... Acknowledgements References

 
Mucosal integrity

The likelihood of acquiring HIV infection following sexual contact is most clearly affected by physical factors, such as the presence of genital ulcerating infections^20,42, which have been proposed to be one of the main reasons for the rapid spread of HIV-1 in sub-Saharan Africa⁴³. Male circumcision is associated with protection from HIV infection 20 (reviewed by Halperin and Bailey⁴⁴), but this can be difficult to disentangle from cultural and religious factors that determine circumcision practice. One potential explanation for a protective role for circumcision is the high frequency of dendritic cells in the mucosa of the foreskin that could provide an accessible pool of HIV-susceptible target cells⁴⁵.

Hormonal factors can also influence mucosal integrity. Macaques treated with depot preparations of progesterone were more susceptible to SIV infection through vaginal exposure⁴⁶, whereas oestrogen had a protective effect⁴⁷. Hormonal influences on infection risk have not been well-studied in humans, but the use of depot progesterone contraception is thought to increase the likelihood of infection⁴⁸.

Genetic factors

Genetic factors also play a role in susceptibility and resistance to HIV infection. The most important of these is a deletion (CCR532) in the major co-receptor for entry of primary HIV strains into CD4⁺ T-cells, a chemokine receptor called CCR5^49,50. Homozygotes for the deletion (1% of Caucasians) do not express the receptor at the cell-surface, and, therefore, can only become infected with strains of HIV that are able to use other co-receptors, such as CXCR4. Thus, although CCR532 homozygotes show a significant degree of resistance to HIV infection, a number of cases of infection with CXCR4-using HIV strains have been reported^51–53. The CCR532 mutation is not found in all races, being largely confined to Caucasians, particularly those of Northern European descent⁵⁴. If the relative levels of CCR5 expression are an important determinant of HIV susceptibility, then it might be expected that CCR532 heterozygotes (who express lower levels of the receptor than most other people⁵⁵) would show a degree of resistance to infection, but this has not been observed in any study. However, cells from highly exposed persistently seronegative (HEPS) donors are often less easy to infect with primary HIV strains, even in the absence of any known CCR5 mutations, and this phenotype is associated with higher production than average of the HIV-suppressing chemokines, MIP-1 MIP-1ß and RANTES 56, which bind to the CCR5 receptor⁵⁷.

Two other polymorphisms in the CCR5 gene have been shown to have an effect on HIV susceptibility. One is a rare point mutation in the coding sequence of CCR5, which in combination with the CCR532 deletion is associated with HIV resistance⁵⁸. The other is a polymorphism in the promoter region (at position 59356), largely confined to people of African descent, which increases the likelihood of infants acquiring HIV infection from their mothers⁵⁹. Although the mechanism is not yet entirely clear, polymorphisms in the promoter region of the gene encoding the HIV-suppressing chemokine RANTES have been recently reported to show an association with HIV susceptibility⁶⁰. Curiously, the same haplotype is linked with prolonged survival in people who do become infected. It has been suggested that this haplotype leads to increased RANTES production which may increase the likelihood of mucosal inflammation and reduced integrity: however, if infection takes place, then higher RANTES levels would suppress HIV replication⁶⁰.

A handful of other genetic polymorphisms have been shown to affect HIV susceptibility. HLA class I and II types have been associated with both resistance and susceptibility to HIV infection. In a cohort of highly-exposed Kenyan sex-workers, HIV resistance is associated with HLA-A2, A^*6802, B18 and DR1, whilst HLA-A23 is associated with increased HIV infection⁶¹. A reduced risk of vertical HIV transmission was seen in infants with particular class II alleles (DRB1^*1501 and DR13)⁶². A number of other genetic associations with HIV resistance have emerged in relatively small studies, including alleles of the TAP (transporters associated with antigen-processing) genes, namely TAP1.4 and TAP2.3⁶³ in the MACS cohort and the non-secretor genotype (which is associated with homozygosity for a stop mutation in the enzyme -(1, 2)-fucosyltransferase, FUT2) in a cohort of Senegalese sex workers (OR 0.18, 95% CI 0.04–0.9)⁶⁴: susceptibility has been associated with variant alleles of the mannose-binding lectin (MBL)⁶⁵, although it was not possible to distinguish between a direct effect on HIV susceptibility and an increased risk of other genital infections known to be affected by MBL genotype.

Immunological mechanisms of HIV resistance

The associations between HLA type and HIV resistance imply that immune responses may be playing a part in resistance to HIV infection, for example if the T-cells using these HLA molecules are particularly efficient at controlling HIV replication. In recent years, a great deal of interest has focused on potential immune mechanisms that may be linked with protection from HIV-1 infection in individuals with documented HIV-1 exposure who remain HIV-1 seronegative, often referred to as highly exposed persistently seronegatives (HEPS). If lymphocytes from HEPS donors are used to reconstitute the immune system of mice with severe combined immunodeficiency (the SCID-Hu mouse model), these animals show resistance to HIV infection, but this is not the case when control donors are used: this protection appears to reside in the CD8⁺ T-cell compartment⁶⁶. A number of studies have shown that a significant proportion of HEPS donors have HIV-specific T-cells in their blood and genital mucosa (reviewed by Kaul and Rowland-Jones⁶⁷). These include CD4⁺ T-cells which show both proliferation⁶⁸ and IL-2 secretion in response to HIV antigens^69–72. HIV-specific CD4⁺ T-cells from HEPS individuals may also secrete HIV-suppressing chemokines^73,74. Many HEPS donors have HLA class I-restricted HIV-specific cytotoxic T lymphocytes (CTL) in both blood (reviewed by Kaul and Rowland-Jones⁶⁷) and genital mucosa⁷⁵. The earliest descriptions of HIV-specific CTL in exposed uninfected individuals came from studies in babies born to infected mothers^76–79, who were likely to have been exposed to HIV for only a brief period around birth. Similar findings came from studies in healthcare workers exposed to HIV-contaminated blood through needlestick injuries⁸⁰80,⁸¹. Similar immune responses have also been described in people with repeated exposure who appeared to be genuinely resistant to infection, such as couples discordant for HIV infection who continue to have unprotected intercourse⁶⁸,^82–85, and sex-workers in parts of the world with high HIV seroprevalence and low condom usage⁸⁶,⁸⁷. These observations suggest that HIV-specific cellular immune responses may be genuinely linked with protection from subsequent infection and has led to efforts to develop HIV-1 vaccines that might induce similar immune responses⁸⁸.

	Early events in primary HIV-1 infection

Top Abstract HIV-1 transmission Factors influencing... Early events in primary... Clinical presentation of primary... Immunopathological events in... Treatment of primary HIV-1... Key points for clinical... Acknowledgements References

 
A better understanding of the early events of HIV-1 infection would seem to be crucial for designing better strategies to prevent or interrupt HIV-1 transmission, yet there is relatively little data about what happens immediately following acute HIV-1 infection in people (Fig.1). One way of addressing these issues is to study events in macaques experimentally infected with the monkey equivalent of HIV, simian immunodeficiency virus (SIV), although these results cannot necessarily always be extrapolated to the human situation. In one such study, only a small number of infected cells were detected in the first 3 days after endocervical infection, close to the site of inoculation. At this stage, the predominant cell population to be infected were T-cells in the lamina propria. Over the next few days, the infection spread to other cell-types, including macrophages and dendritic cells (DCs), but the majority (> 90%) of the infected cells were CD4⁺ T-cells, many of which appeared to be resting T-cells⁸⁹. By day 12, the virus could be found disseminated throughout the lymphatic system and bone marrow.

View larger version (21K): [in this window] [in a new window]   Fig. 1 Diagram to show the likely route of HIV entry and dissemination following primary HIV-1 infection.

 
The role of DCs in early HIV-1 infection is controversial. Some investigators have suggested that DCs are the first cells to become infected in SIV infection⁹⁰, although this has not been confirmed in other studies. DCs provide a highly specialised mechanism whereby an antigen encountered in peripheral tissues, notably skin and mucosal membranes, can be brought into contact with the T-cells in the lymph node that will generate the immune response against it. The principal form of DC in the tissues, exemplified by Langerhans' cells in epithelial and mucosal surfaces, are immature DCs specialised for antigen capture by phagocytosis or pinocytosis. HIV can enter into immature DCs but undergoes only limited replication until the DCs come into contact with T-cells in lymphoid tissue⁹¹. However, there is an additional mechanism which HIV-1 may be able to exploit in the form of a unique lectin called DC-SIGN, which binds to the envelope of HIV-1 with high affinity⁹². When bound to DC-SIGN, the virus can remain viable outside the cell for several days. In this way, the virus could be safely transported to the T-cell rich areas of the lymph nodes, where DC-SIGN is thought to play an important role in activating the responding T-cell population. Since HIV-1 replicates preferentially in activated T-cells, this would provide the virus with a pool of highly susceptible target cells and allow the infection to become established in lymphoid tissue. Although it is very plausible that HIV-1 could subvert the DC system in this way, it is not known how important a mechanism this constitutes in vivo.

Early reports describing the characteristics of virus isolated very early in primary HIV infection showed a remarkable degree of conservation in the envelope gene prior to seroconversion⁹³ suggesting that some degree of selection for HIV envelopes with characteristics particularly suited to transmission was taking place. The viral phenotype early in infection was described as uniformly macrophage-tropic and non-syncitium-inducing⁹⁴, which we now understand to be characteristics of CCR5-using isolates. The reasons why CCR5 usage is required for virus strains to establish primary infection are not entirely understood, but are thought to be related to co-receptor expression on the primary cellular targets of HIV infection, such as CD4⁺ T-cells, DCs and macrophages. It has been generally thought that infection takes place with just a single (often minor) variant from the infected contact⁹⁴, but this derives predominantly from studies in infected men. When similar studies were carried out in Kenyan women, it became clear that the picture was very different. Shortly after infection, these women were shown to be infected by several distinct strains, the first striking demonstration of a gender-based difference in the biology of HIV infection⁹⁵.

	Clinical presentation of primary HIV-1 infection

Top Abstract HIV-1 transmission Factors influencing... Early events in primary... Clinical presentation of primary... Immunopathological events in... Treatment of primary HIV-1... Key points for clinical... Acknowledgements References

 
The clinical syndrome of acute HIV-1 infection was first described 16 years ago as an illness resembling infectious mononucleosis⁹⁶. However, not all patients with primary HIV-1 infection present with this typical clinical picture. One cohort study of the clinical features of acute HIV-1 disease demonstrated that only a minority of patients presented with 'typical' mononucleosis-like symptoms⁹⁷. It is estimated that up to 87% of people undergoing acute HIV infection experience recognisable symptoms⁹⁸, but this could be an overestimate given that this study was carried out in a clinic in which subjects at risk of contracting HIV infection were followed prospectively. Indeed, only 25% of persons in the same cohort received diagnosis of primary HIV infection at their first clinic visit.

Clinical symptoms usually present within days or weeks after primary HIV infection⁹⁹, and may last from a few days up to 10 weeks, although in general the duration is less than 14 days. The most common symptom is fever^98,100,101, which is reported by nearly three-quarters of seroconverting subjects¹⁰⁰,¹⁰¹. Other non-specific symptoms commonly reported include fatigue, headache, myalgia, lymphadenopathy and cutaneous rash¹⁰⁰. The last symptom may be particularly suggestive of primary HIV infection: a maculo-papular skin rash, usually involving the trunk, is found in 40–80% of persons with symptomatic HIV-1 infection. Symptoms may differ in different clinical settings. Although there is a high degree of consistency in Western clinics¹⁰², a carefully-conducted study looking prospectively at signs and symptoms during HIV-1 seroconversion in Kenyan female commercial sex workers reported a quite distinct range of clinical signs and symptoms from those reported in Caucasians (see Table 2)¹⁰¹. Another study in India showed that 81% of patients attending an STD clinic with primary HIV infection had at least one of these eight symptoms: fever, adenopathy, joint pain, thrush, pharyngitis, rash, diarrhoea, and paraesthesia¹⁰³.

View this table: [in this window] [in a new window]   Table 2 Comparison of clinical presentations from two large seroconverter cohorts

 
There is some debate about the prognostic significance of severe clinical manifestations of primary HIV-1 infection. A number of studies have suggested that a more severe illness, particularly with a mononucleosis-like syndrome, may predict more rapid disease progression subsequently^104,105.

The non-specific symptoms of acute HIV infection make it difficult to determine the true frequency of symptomatic illness. This presents a major challenge to healthcare providers, and underscores the need to obtain an accurate history of exposure. Some investigators have proposed criteria to assist in the clinical diagnosis of primary HIV-1 infection by developing a scoring system¹⁰¹. Algorithms to aid clinical diagnosis in this way should help in the selection of patients who warrant further laboratory investigations to confirm or exclude HIV infection, especially in developing countries where sophisticated diagnostic tests are not readily affordable.

In industrialised countries, laboratory tests help to confirm the diagnosis of acute HIV infection. Conventional serological testing is often negative for a window period of approximately 22–27 days after the initial infection¹⁰⁶. Detection of either plasma or serum p24 antigen is normally recommended for diagnosis for acute HIV infection and for screening of blood donors who may unintentionally donate contaminated blood if tested by serology during the window period. Rarely, the p24 antigen assays may give false-negative results¹⁰⁷. In this prospective cohort study, the sensitivity and specificity of p24 antigen detection assays were estimated to be 88.7% and 100%, respectively. Interestingly, the false-negative results from these patients were not because the HIV RNA viral load was low: the mean level of HIV RNA in 5 patients who had primary HIV infection but undetectable p24 antigen was 251,189 copies/ml (range 100,000–630,957 copies/ml). On the other hand, the detection of HIV RNA by viral load assays, which gives a sensitivity of 100% and specificity of 97.4%, may be a more prudent screening method to detect primary HIV infection. This method has also proved to be cost-effective in screening pooled serum or plasma from blood donors¹⁰⁸. Suspected cases should then be confirmed by p24 antigen detection, which is more specific. However, HIV RNA assays are relatively time-consuming, expensive and need sophisticated technology, which pose significant problems for non-industrialised countries.

	Immunopathological events in primary HIV-1 infection

Top Abstract HIV-1 transmission Factors influencing... Early events in primary... Clinical presentation of primary... Immunopathological events in... Treatment of primary HIV-1... Key points for clinical... Acknowledgements References

 
Once infection with HIV-1 has become established in the lymphoid tissues, there is extensive virus replication, which is soon reflected in very high levels of plasma viraemia¹⁰⁹. The peak viraemia occurs an average of 6–15 days after the onset of symptoms¹¹⁰, with viral load levels of 1–10 million/copies/ml¹¹¹, at which time the donor is probably highly infectious³³. During this period, extensive viral seeding takes place, so that the virus disseminates widely through lymphoid and other tissues¹¹². In lymphoid tissue, the virus particles can become trapped in the follicular dendritic cell (FDC) network¹¹³, so that during the asymptomatic period, the viral burden is much higher in the lymph nodes than in the blood. The very high levels of plasma viraemia are generally short-lived¹⁰⁹,¹¹⁰, suggesting that the host is able to generate an immune response which controls viral replication. Over the next few weeks, the plasma virus load falls by several orders of magnitude, although antibodies with the capacity to neutralise the virus are rarely detected at this stage¹¹⁴,¹¹⁵. It is thought that the cellular immune response is largely responsible for the early control of HIV replication¹¹⁶. There is a profound CD8⁺ T-cell lymphocytosis, with massive oligoclonal expansions (representing up to 40% of all T cells), which express activation markers like CD38, CD27 and HLA-DR but are CD28 negative¹¹⁷. In culture these CD8⁺ CD28^- cells are primed for apoptosis¹¹⁸, and are thought to represent terminally differentiated effector cytotoxic T lymphocytes (CTL)¹¹⁹. Virus-specific CTL have been described as early as 2 days after clinical presentation, and can generally be detected within weeks of the onset of symptoms¹¹⁵,¹²⁰,¹²¹. Using soluble class I HLA-B27 molecules assembled with HIV peptides as ‘tetramers’, it could be shown that as many as 5% of circulating CD8⁺ T-cells were specific for a single HIV gag epitope¹²²: using other tetramers we have seen responses as high as 10% of CD8⁺ T-cells in patients undergoing primary HIV-1 infection (unpublished observations). Studies of the T-cell receptor (TCR) repertoire in primary HIV infection have shown that the CD8⁺ response is represented by large but transient oligoclonal expansions in many patients¹¹⁹.

In some studies, a few donors failed to make a detectable CTL response, and these patients exhibited a rapidly progressive course of HIV infection without control of virus levels¹¹⁵,¹²⁰, suggesting that the early generation of a vigorous HIV-specific CTL response may not only be responsible for the initial control of viraemia but also influence the subsequent disease course. In one study, a high frequency of envelope-specific CTL during acute HIV infection was associated with a significantly lower HIV-1 viral load subsequently¹²³ A particularly narrow repertoire of CD8⁺ expansions is also associated with a poor prognosis¹²⁴: this implies that a relatively limited CD8⁺ response could facilitate viral escape from the immune system or lead to more rapid immune exhaustion^119,125. The selection of virus variants that have acquired changes in the epitopes recognised by the dominant acute CTL response, sufficient to abrogate CTL recognition, is now well-described in both acutely infected people^126,127 and monkeys infected with cloned SIV¹²⁸: this may contribute to the ultimate failure of the immune response to contain viral replication in HIV-1 infection.

During primary infection, the CD4 count falls, and occasionally it may be sufficiently depressed to allow the development of opportunistic infections^129,130. The initial loss of CD4⁺ T-cells is mainly concentrated in the CCR5 negative subset¹³¹. CD4⁺ T cell function is also markedly abnormal¹³². Even though the CD4⁺ count may rebound with the resolution of primary infection, it rarely returns to baseline. It is then relatively stable during the asymptomatic period, but in untreated HIV infection shows an abrupt decline late in disease, shortly before the onset of symptoms. CD4⁺ T-cell function remains abnormal throughout the course of HIV infection^133–135. Qualitative loss of CD4⁺ T-cell help, first to HIV antigens and then to other recall antigens, is perhaps the most characteristic abnormality detected throughout HIV infection^69,135,136. The deletion of HIV-specific helper responses seems most likely to occur early in primary HIV infection, when presumably CD4⁺ T-cells responding to HIV antigens are not only highly activated but also localised to sites of HIV replication, making them prime targets for HIV infection. Following the initial reduction of viraemia, a viral ‘set-point’ is established at around 12–18 months after infection, the level of which is closely related to the ultimate clinical outcome in HIV disease¹³⁷.

	Treatment of primary HIV-1 infection

Top Abstract HIV-1 transmission Factors influencing... Early events in primary... Clinical presentation of primary... Immunopathological events in... Treatment of primary HIV-1... Key points for clinical... Acknowledgements References

 
With increasing early diagnosis of primary HIV-1 infection, it has become possible recently to investigate the effect of prompt institution of anti-retroviral therapy. The early reports have been encouraging, with data to show that patients treated very early in infection can recover or retain HIV-specific CD4⁺ T-cell responses whilst maintaining an effective CD8⁺ T-cell response^136,138. Other investigators have raised concerns that if therapy is initiated too early then the immune system does not generate a full response to HIV antigens^139,140. One promising strategy to counteract these concerns is to allow carefully controlled viral replication using supervised treatment interruptions following initial aggressive therapy: early reports suggest that patients treated in this way develop a broader HIV-specific CTL response and may be able to control viral load without therapy¹⁴¹.

	Key points for clinical practice

Top Abstract HIV-1 transmission Factors influencing... Early events in primary... Clinical presentation of primary... Immunopathological events in... Treatment of primary HIV-1... Key points for clinical... Acknowledgements References

 

• The likelihood of HIV-1 transmission is generally predicted by plasma viral load, but can still occur from people with good viral suppression on therapy.
  
• Genital ulcer disease is a potent co-factor for HIV-1 transmission
  
• Antibody tests may be negative for several weeks after primary infection: the best method of diagnosis of acute HIV infection is plasma RNA combined with a p24 antigen test
  
• Early treatment of primary HIV-1 infection with anti-retroviral therapy appears to provide the best hope of preserving immune function in infected people
  

	Acknowledgements

Top Abstract HIV-1 transmission Factors influencing... Early events in primary... Clinical presentation of primary... Immunopathological events in... Treatment of primary HIV-1... Key points for clinical... Acknowledgements References

 
The authors acknowledge the support of the Medical Research Council and the Elizabeth Glaser Paediatric AIDS Foundation. SR-J is an Elizabeth Glaser Scientist of the Paediatric AIDS Foundation.

	Footnotes

 
Correspondence to: Prof. Sarah Rowland-Jones, Human Immunology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK

	References

Top Abstract HIV-1 transmission Factors influencing... Early events in primary... Clinical presentation of primary... Immunopathological events in... Treatment of primary HIV-1... Key points for clinical... Acknowledgements References

 

1. Padian NS, Shiboski SC, Glass SO, Vittinghoff E. Heterosexual transmission of human immunodeficiency virus (HIV) in northern California: results from a ten-year study. Am J Epidemiol 1997; 146: 350–7[Abstract/Free Full Text]
2. Caceres CF, van Griensven GJ. Male homosexual transmission of HIV-1. AIDS 1994; 8: 1051–61[Web of Science][Medline]
3. Datta P, Embree JE, Kreiss J et al. Mother-to-child transmission of HIV-1 : report from the Nairobi study. J Infect Dis 1994; 170: 1134–40[Web of Science][Medline]
4. Nduati R. Breastfeeding and HIV-1 infection. A review of current literature. Adv Exp Med Biol 2000; 478: 201–10[Web of Science][Medline]
5. Baba TW, Jeong YS, Pennick D, Bronson R, Greene MF, Ruprecht RM. Pathogenicity of live, attenuated SIV after mucosal infection of neonatal macaques. Science 1995; 267: 1820–5[Abstract/Free Full Text]
6. Stahl-Hennig C, Steinman RM, Tenner-Racz K et al. Rapid infection of oral mucosal-associated lymphoid tissue with simian immunodeficiency virus. Science 1999; 285: 1261–5[Abstract/Free Full Text]
7. Gershon RR, Vlahov D, Nelson KE. The risk of transmission of HIV-1 through non-percutaneous, non-sexual modes – a review. AIDS 1990; 4: 645–50[Web of Science][Medline]
8. Fitzgibbon JE, Gaur S, Frenkel LD, Laraque F, Edlin BR, Dubin DT. Transmission from one child to another of human immunodeficiency virus type 1 with a zidovudine-resistance mutation. N Engl J Med 1993; 329: 1835–41[Abstract/Free Full Text]
9. Belec L, Si Mohamed A, Muller-Trutwin MC et al. Genetically related human immunodeficiency virus type 1 in three adults of a family with no identified risk factor for intrafamilial transmission. J Virol 1998; 72: 5831–9[Abstract/Free Full Text]
10. Schreiber GB, Busch MP, Kleinman SH, Korelitz JJ. The risk of transfusion-transmitted viral infections. The Retrovirus Epidemiology Donor Study. N Engl J Med 1996; 334: 1685–90[Abstract/Free Full Text]
11. Cardo DM, Culver DH, Ciesielski CA et al. A case-control study of HIV seroconversion in health care workers after percutaneous exposure. Centers for Disease Control and Prevention Needlestick Surveillance Group. N Engl J Med 1997; 337: 1485–90[Abstract/Free Full Text]
12. Peterman TA, Stoneburner RL, Allen JR, Jaffe HW, Curran JW. Risk of human immunodeficiency virus transmission from heterosexual adults with transfusion-associated infections. JAMA 1988; 259: 55–8[Abstract/Free Full Text]
13. Wiley JA, Herschkorn SJ, Padian NS. Heterogeneity in the probability of HIV transmission per sexual contact: the case of male-to-female transmission in penile-vaginal intercourse. Stat Med 1989; 8: 93–102[Web of Science][Medline]
14. Padian N, Marquis L, Francis DP et al. Male-to-female transmission of human immunodeficiency virus. JAMA 1987; 258: 788–90[Abstract/Free Full Text]
15. Fischl MA, Dickinson GM, Scott GB, Klimas N, Fletcher MA, Parks W. Evaluation of heterosexual partners, children, and household contacts of adults with AIDS. JAMA 1987; 257: 640–4[Abstract/Free Full Text]
16. Downs AM, De Vincenzi I. Probability of heterosexual transmission of HIV: relationship to the number of unprotected sexual contacts. European Study Group in Heterosexual Transmission of HIV. J Acquir Immune Defic Syndr Hum Retrovirol 1996; 11: 388–95[Web of Science][Medline]
17. Duerr A, Nagachinta T, Tovanabutra S, Tansuhaj AKN. Probability of male-to-female HIV transmission among married couples in Chiang Mai, Thailand. Tenth International Conference on AIDS, Yokohama, Japan 1994; Abstract 105C
18. Mastro TD, Satten GA, Nopkesorn T, Sangkharomya S, Longini IM. Probability of female-to-male transmission of HIV-1 in Thailand. Lancet 1994; 343: 204–7[Web of Science][Medline]
19. Satten GA, Mastro TD, Longini IM. Modelling the female-to-male per-act HIV transmission probability in an emerging epidemic in Asia. Stat Med 1994; 13: 2097–106[Web of Science][Medline]
20. Cameron DW, Simonsen JN, D'Costa LJ et al. Female to male transmission of human immunodeficiency virus type 1: risk factors for seroconversion in men. Lancet 1989; ii: 403–7
21. DeGruttola V, Seage 3rd GR, Mayer KH, Horsburgh Jr CR. Infectiousness of HIV between male homosexual partners. J Clin Epidemiol 1989; 42: 849–56[Web of Science][Medline]
22. Shaffer N, Chuachoowong R, Mock PA et al. Short-course zidovudine for perinatal HIV-1 transmission in Bangkok, Thailand: a randomised controlled trial. Bangkok Collaborative Perinatal HIV Transmission Study Group. Lancet 1999; 353: 773–80[Web of Science][Medline]
23. Wiktor SZ, Ekpini E, Karon JM et al. Short-course oral zidovudine for prevention of mother-to-child transmission of HIV-1 in Abidjan, Cote d'Ivoire: a randomised trial. Lancet 1999; 353: 781–5[Web of Science][Medline]
24. The International Perinatal HIV Group. The mode of delivery and the risk of vertical transmission of human immunodeficiency virus type 1 – a meta-analysis of 15 prospective cohort studies. N Engl J Med 1999; 340: 977–87[Abstract/Free Full Text]
25. Nduati R, John G, Mbori-Ngacha D et al. Effect of breastfeeding and formula feeding on transmission of HIV-1: a randomized clinical trial. JAMA 2000; 283: 1167–74[Abstract/Free Full Text]
26. Pungpapong S, Phanuphak P, Pungpapong K, Ruxrungtham K. The risk of occupational HIV exposure among Thai healthcare workers. Southeast Asian J Trop Med Public Health 1999; 30: 496–503[Medline]
27. de Graaf R, Houweling H, van Zessen G. Occupational risk of HIV infection among western health care professionals posted in AIDS endemic areas. AIDS Care 1998; 10: 441–52[Web of Science][Medline]
28. Gumodoka B, Favot I, Berege ZA, Dolmans WM. Occupational exposure to the risk of HIV infection among health care workers in Mwanza Region, United Republic of Tanzania. Bull World Health Organ 1997; 75: 133–40[Web of Science][Medline]
29. Cohen ND, Munoz A, Reitz BA et al. Transmission of retroviruses by transfusion of screened blood in patients undergoing cardiac surgery. N Engl J Med 1989; 320: 1172–6[Abstract]
30. Gerst PH, Fildes JJ, Rosario PG, Schorr JB. Risks of human immunodeficiency virus infection to patients and healthcare personnel. Crit Care Med 1990; 18: 1440–8[Web of Science][Medline]
31. Lackritz EM. Prevention of HIV transmission by blood transfusion in the developing world: achievements and continuing challenges. AIDS 1998; 12: S81–6
32. Matz B, Kupfer B, Ko Y et al. HIV-1 infection by artificial insemination. Lancet 1998; 351: 728[Web of Science][Medline]
33. Quinn TC, Wawer MJ, Sewankambo N et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N Engl J Med 2000; 342: 921–9[Abstract/Free Full Text]
34. John GC, Nduati RW, Mbori-Ngacha D et al. Genital shedding of human immunodeficiency virus type 1 DNA during pregnancy: association with immunosuppression, abnormal cervical or vaginal discharge, and severe vitamin A deficiency. J Infect Dis 1997; 175: 57–62[Web of Science][Medline]
35. Mostad SB, Jackson S, Overbaugh J et al. Cervical and vaginal shedding of human immunodeficiency virus type 1- infected cells throughout the menstrual cycle. J Infect Dis 1998; 178: 983–91[Web of Science][Medline]
36. Zhang H, Dornadula G, Beumont M et al. Human immunodeficiency virus type 1 in the semen of men receiving highly active antiretroviral therapy. N Engl J Med 1998; 339: 1803–9[Abstract/Free Full Text]
37. John GC, Rousseau C, Dong T et al. Maternal SDF1 3'A polymorphism is associated with increased perinatal human immunodeficiency virus type 1 transmission [In Process Citation]. J Virol 2000; 74: 5736–9[Abstract/Free Full Text]
38. Vernazza PL, Eron JJ, Fiscus SA, Cohen MS. Sexual transmission of HIV: infectiousness and prevention. AIDS 1999; 13: 155–66[Web of Science][Medline]
39. Soto-Ramirez LE, Renjifo B, McLane MF et al. HIV-1 Langerhans' cell tropism associated with heterosexual transmission of HIV [see comments]. Science 1996; 271: 1291–3[Abstract]
40. Pope M, Frankel SS, Mascola JR et al. Human immunodeficiency virus type 1 strains of subtypes B and E replicate in cutaneous dendritic cell-T-cell mixtures without displaying subtype-specific tropism. J Virol 1997; 71: 8001–7[Abstract/Free Full Text]
41. Whittle HC, Ariyoshi K, Rowland-Jones S. HIV-2 and T cell recognition. Curr Opin Immunol 1998; 10: 382–7[Web of Science][Medline]
42. Simonsen JN, Plummer FA, Ngugi EN et al. HIV infection among lower socioeconomic strata prostitutes in Nairobi. AIDS 1990; 4: 139–44[Web of Science][Medline]
43. Hayes RJ, Schulz KF, Plummer FA. The cofactor effect of genital ulcers on the per-exposure risk of HIV transmission in sub-Saharan Africa. J Trop Med Hyg 1995; 98: 1–8[Web of Science][Medline]
44. Halperin DT, Bailey RC. Male circumcision and HIV infection: 10 years and counting. Lancet 1999; 354: 1813–5[Web of Science][Medline]
45. Hussain LA, Lehner T. Comparative investigation of Langerhans' cells and potential receptors for HIV in oral, genitourinary and rectal epithelia. Immunology 1995; 85: 475–84[Web of Science][Medline]
46. Marx PA, Spira AI, Gettie A et al. Progesterone implants enhance SIV vaginal transmission and early virus load. Nat Med 1996; 2: 1084–9[Web of Science][Medline]
47. Smith SM, Baskin GB, Marx PA. Estrogen protects against vaginal transmission of simian immunodeficiency virus. J Infect Dis 2000; 182: 708–15[Web of Science][Medline]
48. Martin HL, Nyange PM, Richardson BA et al. Hormonal contraception, sexually transmitted diseases, and risk of heterosexual transmission of human immunodeficiency virus type 1. J Infect Dis 1998; 178: 1053–9[Web of Science][Medline]
49. Liu R, Paxton WA, Choe S et al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 1996; 88: 7–20
50. Samson M, Libert F, Doranz BJ et al. Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 1996; 382: 722–5[Medline]
51. O'Brien T, Winkler C, Dean M et al. HIV-1 infection in a man homozygous for CCR532. Lancet 1997; 349: 1219[Medline]
52. Biti R, French R, Young J, Bennetts B, Stewart G. HIV-1 infection in an individual homozygous for the CCR5 deletion allele. Nat Med 1997; 3: 252–3[Web of Science][Medline]
53. Balotta C, Bagnarelli P, Violin M et al. Homozygous delta 32 deletion of the CCR-5 chemokine receptor gene in an HIV-1-infected patient. AIDS 1997; 11: F67–F71[Web of Science][Medline]
54. Martinson JJ, Chapman NH, Rees DC, Liu Y-T, Clegg JB. Global distribution of the CCR5 gene 32 base-pair deletion. Nat Genet 1997; 16: 100–3[Web of Science][Medline]
55. Wu L, Paxton WA, Kassam N et al. CCR5 levels and expression pattern correlate with infectability by macrophage-tropic HIV-1 in vitro. J Exp Med 1997; 185: 1681–92[Abstract/Free Full Text]
56. Cocchi F, DeVico AL, Garzino DA, Arya SK, Gallo RC, Lusso P. Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8⁺ T cells. Science 1995; 270: 1811–5[Abstract/Free Full Text]
57. Paxton WA, Liu R, Kang S et al. Reduced HIV-1 infectability of CD4⁺ lymphocytes from exposed-uninfected individuals: association with low expression of CCR5 and high production of beta-chemokines. Virology 1998; 244: 66–73[Web of Science][Medline]
58. Quillent C, Oberlin E, Braun J et al. HIV-1-resistance phenotype conferred by combination of two separate inherited mutations of CCR5 gene. Lancet 1997; 351: 14–8
59. Kostrikis LG, Neumann AU, Thomson B et al. A polymorphism in the regulatory region of the CC-chemokine receptor 5 gene influences perinatal transmission of human immunodeficiency virus type 1 to African-American infants. J Virol 1999; 73: 10264–71[Abstract/Free Full Text]
60. McDermott DH, Zimmerman PA, Guignard F, Kleeberger CA, Leitman SF, Murphy PM. CCR5 promoter polymorphism and HIV-1 disease progression. Multicenter AIDS Cohort Study (MACS). Lancet 1998; 352: 866–70[Web of Science][Medline]
61. MacDonald KS, Fowke KR, Kimani J et al. Influence of HLA supertypes on susceptibility and resistance to human immunodeficiency virus type 1 infection. J Infect Dis 2000; 181: 1581–9[Web of Science][Medline]
62. Winchester R, Chen Y, Rose S, Selby J, Borkowsky W. Major histocompatibility complex class II DR alleles DRB1^*1501 and those encoding HLA-DR13 are preferentially associated with a diminution in maternally transmitted human immunodeficiency virus 1 infection in different ethnic groups: determination by an automated sequence-based typing method. Proc Natl Acad Sci USA 1995; 92: 12374–8[Abstract/Free Full Text]
63. Detels R, Mann D, Carrington M et al. Resistance to HIV-1 may be genetically mediated. AIDS 1996; 10: 102–4[Web of Science][Medline]
64. Ali S, Niang MA, N'Doye I et al. Secretor polymorphism and human immunodeficiency virus infection in Senegalese women. J Infect Dis 2000; 181: 737–9[Web of Science][Medline]
65. Garred P, Madsen HO, Balslev U et al. Susceptibility to HIV infection and progression of AIDS in relation to variant alleles of mannose-binding lectin. Lancet 1997; 349: 236–40[Web of Science][Medline]
66. Zhang C, Cui Y, Houston S, Chang LJ. Protective immunity to HIV-1 in SCID/beige mice reconstituted with peripheral blood lymphocytes of exposed but uninfected individuals. Proc Natl Acad Sci USA 1996; 93: 14720–5[Abstract/Free Full Text]
67. Kaul R, Rowland-Jones SL. Methods of detection of HIV-specific CTL and their role in protection against HIV infection. In: Korber B, Brander C, Haynes BF et al.(eds) HIV Molecular Immunology Database. Los Alamos, NM: Los Alamos National Laboratory, Theoretical Biology and Biophysics, 1999; IV-35-44
68. Goh WC, Markee J, Akridge RE et al. Protection against human immunodeficiency virus type 1 infection in persons with repeated exposure: evidence for T cell immunity in the absence of inherited CCR5 coreceptor defects. J Infect Dis 1999; 179: 548–57[Web of Science][Medline]
69. Clerici M, Shearer G. A Th1-> Th2 switch is a critical step in the aetiology of HIV infection. Immunol Today 1993; 14: 107–11[Web of Science][Medline]
70. Clerici M, Sison AV, Berzofsky JA et al. Cellular immune factors associated with mother-to-infant transmission of HIV. AIDS 1993; 7: 1427–33[Web of Science][Medline]
71. Clerici M, Levin JM, Kessler HA et al. HIV-specific T-helper activity in seronegative health care workers exposed to contaminated blood. JAMA 1994; 271: 42–6[Abstract/Free Full Text]
72. Beretta A, Furci L, Burastero S et al. HIV-1-specific immunity in persistently seronegative individuals at high risk for HIV infection. Immunol Lett 1996; 51: 39–43[Web of Science][Medline]
73. Furci L, Scarlatti G, Burastero S et al. Antigen-driven C-C chemokine-mediated HIV-1 suppression by CD4(+) T cells from exposed uninfected individuals expressing the wild-type CCR-5 allele. J Exp Med 1997; 186: 455–60[Abstract/Free Full Text]
74. Wasik TJ, Bratosiewicz J, Wierzbicki A et al. Protective role of beta-chemokines associated with HIV-specific Th responses against perinatal HIV transmission. J Immunol 1999; 162: 4355–64[Abstract/Free Full Text]
75. Kaul R, Plummer FA, Kimani J et al. HIV-1-specific mucosal CD8⁺ lymphocyte responses in the cervix of HIV-1-resistant prostitutes in Nairobi. J Immunol 2000; 164: 1602–11[Abstract/Free Full Text]
76. Cheynier R, Langlade-Demoyen P, Marescot M-R et al. Cytotoxic T lymphocyte responses in the peripheral blood of children born to HIV-1-infected mothers. Eur J Immunol 1992; 22: 2211–7[Web of Science][Medline]
77. Rowland-Jones SL, Nixon DF, Aldhous MC et al. HIV-specific CTL activity in an HIV-exposed but uninfected infant. Lancet 1993; 341: 860–1[Web of Science][Medline]
78. Aldhous MC, Watret KC, Mok JY, Bird AG, Froebel KS. Cytotoxic T lymphocyte activity and CD8 subpopulations in children at risk of HIV infection. Clin Exp Immunol 1994; 97: 61–7[Web of Science][Medline]
79. De Maria A, Cirillo C, Moretta L. Occurrence of HIV-specific CTL activity in apparently uninfected children born to HIV-1-infected mothers. J Infect Dis 1994; 170: 1296–9[Web of Science][Medline]
80. Pinto LA, Sullivan J, Berzofsky JA et al. ENV-specific cytotoxic T lymphocyte responses in HIV seronegative health care workers occupationally exposed to HIV-contaminated body fluids. J Clin Invest 1995; 96: 867–76[Web of Science][Medline]
81. Pinto LA, Covas MJ, Victorino RM. T-helper cross reactivity to viral recombinant proteins in HIV-2-infected patients [Published erratum appears in AIDS 1993; 7: following 1541]. AIDS 1993; 7: 1389–91[Web of Science][Medline]
82. Langlade-Demoyen P, Ngo-Giang-Huong N, Ferchal F, Oksenhendler E. HIV nef-specific cytotoxic T lymphocytes in noninfected heterosexual contact of HIV-infected patients. J Clin Invest 1994; 93: 1293–7[Web of Science][Medline]
83. Mazzoli S, Trabbatoni D, Lo Caputo S et al. HIV-specific mucosal and cellular immunity in HIV-seronegative partners of HIV-seropositive individuals. Nat Med 1997; 3: 1250–7[Web of Science][Medline]
84. Bernard NF, Yannakis CM, Lee JS, Tsoukas CM. Human immunodeficiency virus (HIV)-specific cytotoxic T lymphocyte activity in HIV-exposed seronegative persons. J Infect Dis 1999; 179: 538–47[Web of Science][Medline]
85. Bienzle D, MacDonald KS, Smaill FM et al. Factors contributing to the lack of human immunodeficiency virus type 1 (HIV-1) transmission in HIV-1-discordant partners [In Process Citation]. J Infect Dis 2000; 182: 123–32[Web of Science][Medline]
86. Rowland-Jones SL, Sutton J, Ariyoshi K et al. HIV-specific cytotoxic T cells in HIV-exposed but uninfected Gambian women. Nat Med 1995; 1: 59–64[Web of Science][Medline]
87. Rowland-Jones SL, Dong T, Fowke KR et al. Cytotoxic T cell responses to multiple conserved HIV epitopes in HIV-resistant prostitutes in Nairobi. J Clin Invest 1998; 102: 1758–65[Web of Science][Medline]
88. Hanke T, McMichael AJ. Design and construction of an experimental HIV-1 vaccine for a year 2000 clinical trial in Kenya. Nat Med 2000; 6: 951–5[Web of Science][Medline]
89. Zhang Z, Schuler T, Zupancic M et al. Sexual transmission and propagation of SIV and HIV in resting and activated CD4(₊) T cells. Science 1999; 286: 1353–7[Abstract/Free Full Text]
90. Spira AI, Marx PA, Patterson BK et al. Cellular targets of infection and route of viral dissemination after an intravaginal inoculation of simian immunodeficiency virus into rhesus macaques. J Exp Med 1996; 183: 215–25[Abstract/Free Full Text]
91. Granelli-Piperno A, Finkel V, Delgado E, Steinman RM. Virus replication begins in dendritic cells during the transmission of HIV-1 from mature dendritic cells to T cells. Curr Biol 1999; 9: 21–9[Web of Science][Medline]
92. Giejtenbeek T, Kwon D, Torensma R et al. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T-cells. Cell 2000; 100: 587–97[Web of Science][Medline]
93. Zhang LQ, MacKenzie P, Cleland A, Holmes EC, Leigh Brown AJ, Simmonds P. Selection for specific sequences in the external envelope protein of HIV-1 upon primary infection. J Virol 1993; 67: 3345–56[Abstract/Free Full Text]
94. Zhu T, Mo H, Wang N et al. Genotypic and phenotypic characterization of HIV-1 in patients with primary infection. Science 1993; 261: 1179–81[Abstract/Free Full Text]
95. Long EM, Martin Jr HL, Kreiss JK et al. Gender differences in HIV-1 diversity at time of infection. Nat Med 2000; 6: 71–5[Web of Science][Medline]
96. Cooper D, Gold J, Maclean P et al. Acute AIDS retrovirus infection. Definition of a clinical illness associated with seroconversion. Lancet 1985; i: 537–40
97. Vanhems P, Allard R, Cooper DA et al. Acute human immunodeficiency virus type 1 disease as a mononucleosis-like illness: is the diagnosis too restrictive? Clin Infect Dis 1997; 24: 965–70[Web of Science][Medline]
98. Schacker T, Collier AC, Hughes J, Shea T, Corey L. Clinical and epidemiological features of primary HIV infection. Ann Intern Med 1996; 125: 257–64[Abstract/Free Full Text]
99. Kahn JO, Walker BD. Acute human immunodeficiency virus type 1 infection. N Engl J Med 1998; 339: 33–9[Free Full Text]
100. Vanhems P, Dassa C, Lambert J, et al. Comprehensive classification of symptoms and signs reported among 218 patients with acute HIV-1 infection. J Acquir Immune Defic Syndr 1999; 21: 99–106[Web of Science][Medline]
101. Lavreys L, Thompson ML, Martin Jr HL et al. Primary human immunodeficiency virus type 1 infection: clinical manifestations among women in Mombasa, Kenya. Clin Infect Dis 2000; 30: 486–90[Web of Science][Medline]
102. Vanhems P, Hughes J, Collier AC et al. Comparison of clinical features, CD4 and CD8 responses among patients with acute HIV-1 infection from Geneva, Seattle and Sydney. AIDS 2000; 14: 375–81[Web of Science][Medline]
103. Bollinger RC, Brookmeyer RS, Mehendale SM et al. Risk factors and clinical presentation of acute primary HIV infection in India. JAMA 1997; 278: 2085–9[Abstract/Free Full Text]
104. Pedersen C, Lindhardt BO, Jensen BL et al. Clinical course of primary HIV infection: consequences for subsequent course of infection. BMJ 1989; 299: 154–7[Abstract/Free Full Text]
105. Lindback S, Brostrom C, Karlssom A, Gaines H. Does symptomatic primary HIV-1 infection accelerate progression to CDC stage IV disease, CD4 count below 200 x 10⁶/ml, AIDS, and death from AIDS? BMJ 1994; 309: 1535–7[Abstract/Free Full Text]
106. Busch MP, Lee LL, Satten GA et al. Time course of detection of viral and serologic markers preceding human immunodeficiency virus type 1 seroconversion: implications for screening of blood and tissue donors. Transfusion 1995; 35: 91–7[Web of Science][Medline]
107. Daar ES, Little S, Pitt J et al. Diagnosis of primary HIV-1 infection. Los Angeles County Primary HIV Infection Recruitment Network. Ann Intern Med 2001; 134: 25–9[Abstract/Free Full Text]
108. Roth WK, Weber M, Seifried E. Feasibility and efficacy of routine PCR screening of blood donations for hepatitis C virus, hepatitis B virus, and HIV-1 in a blood-bank setting. Lancet 1999; 353: 359–63[Web of Science][Medline]
109. Daar ES, Moudgil T, Meyer RD, Ho DD. Transient high levels of viremia in patients with primary human immunodeficiency virus type 1 infection. N Engl J Med 1991; 324: 961–4[Abstract]
110. Clark SJ, Saag MS, Decker WD et al. High titers of cytopathic virus in plasma of patients with symptomatic primary HIV-1 infection. N Engl J Med 1991; 324: 954–60[Abstract]
111. Piatak M, Saag M, Yang L. High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science 1993; 259: 1749–54[Abstract/Free Full Text]
112. Pantaleo G, Graziosi C, Demarest JF et al. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature 1993; 362: 355–8[Medline]
113. Spiegel H, Herbst H, Niedobitek G, Foss HD, Stein H. Follicular dendritic cells are a major reservoir for human immunodeficiency virus type 1 in lymphoid tissues facilitating infection of CD4⁺ T-helper cells. Am J Pathol 1992; 140: 15–22[Abstract]
114. Ariyoshi K, Harwood E, Chiengsong-Popov R, Weber J. Is clearance of HIV-1 viraemia at seroconversion mediated by neutralising antibodies ? Lancet 1992; 340: 1257–8[Web of Science][Medline]
115. Koup RA, Safrit JT, Cao Y et al. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol 1994; 68: 4650–5[Abstract/Free Full Text]
116. Koup RA, Ho DD. Shutting down HIV. Nature 1994; 370: 416[Medline]
117. Roos M, De Leeuw N, Claessen F et al. Viro-immunological studies in acute HIV-1 infection. AIDS 1994; 8: 1533–8[Web of Science][Medline]
118. Brugnoni D, Prati E, Malacarne F, Gorla R, Airo P, Cattaneo R. The primary response to HIV infection is characterised by an expansion of activated CD8⁺ CD28-cells. AIDS 1996; 10: 104–6[Web of Science][Medline]
119. Pantaleo G, Demarest JF, Soudeyns H et al. Major expansion of CD8⁺ T cells with a predominant Vb usage during the primary immune response to HIV. Nature 1994; 370: 463–7[Medline]
120. Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MB. Virus-specific CD8⁺ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J Virol 1994; 68: 6103–10[Abstract/Free Full Text]
121. Lamhamedi-Cherradi S, Culmann-Penciolelli B, Guy B et al. Different patterns of HIV-1-specific cytotoxic T-lymphocyte activity after primary infection. AIDS 1995; 9: 421–6[Web of Science][Medline]
122. Wilson JD, Ogg GS, Allen RL et al. Direct visualization of HIV-1-specific cytotoxic T lymphocytes during primary infection. AIDS 2000; 14: 225–33[Web of Science][Medline]
123. Musey L, Hughes J, Schacker T, Shea T, Corey L, McElrath MJ. Cytotoxic-T-cell responses, viral load, and disease progression in early human immunodeficiency virus type 1 infection. N Engl J Med 1997; 337: 1267–74[Abstract/Free Full Text]
124. Pantaleo G, Demarest JF, Schacker T et al. The qualitative nature of the primary immune response to HIV infection is a prognosticator of disease progression independent of the initial level of plasma viremia. Proc Natl Acad Sci USA 1997; 94: 254–8[Abstract/Free Full Text]
125. Safrit JT, Koup RA. The immunology of primary HIV infection: which immune responses control HIV replication? Curr Opin Immunol 1995; 7: 456–61[Web of Science][Medline]
126. Price DA, Goulder PJ, Klenerman P et al. Positive selection of HIV-1 cytotoxic T lymphocyte escape variants during primary infection. Proc Natl Acad Sci USA 1997; 94: 1890–5[Abstract/Free Full Text]
127. Kelleher AD, Long C, Holmes EC et al. Clustered mutations in HIV-1 gag are consistently required for escape from HLA-B27-restricted cytotoxic T lymphocyte responses. J Exp Med 2001; 193: 375–86[Abstract/Free Full Text]
128. Allen TM, O'Connor DH, Jing P, et al. Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia. Nature 2000; 407: 386–90[Medline]
129. Gupta KK. Acute immunosuppression with HIV seroconversion. N Engl J Med 1993; 328: 228–9[Abstract/Free Full Text]
130. Vento S, Di PG, Garofano T, Concia E, Bassetti D. Pneumocystis carinii pneumonia during primary HIV-1 infection. Lancet 1993; 342: 24–5[Web of Science][Medline]
131. Zaunders JJ, Kaufmann GR, Cunningham PH et al. Increased turnover of CCR5⁺ and redistribution of CCR5^- CD4 T lymphocytes during primary human immunodeficiency virus type 1 infection. J Infect Dis 2001; 183: 736–43[Web of Science][Medline]
132. Pedersen C, Dickmeiss E, Gaub J et al. T-cell subset alterations and lymphocyte responsiveness to mitogens and antigen during severe primary infection with HIV: a case series of seven consecutive HIV seroconverters. AIDS 1990; 4: 523–6[Web of Science][Medline]
133. Musey LK, Kreiger JN, Hughes JP, Schacker TW, Corey L, McElrath MJ. Early and persistent human immunodeficiency virus type 1 (HIV-1)-specific T helper dysfunction in blood and lymph nodes following acute HIV-1 infection. J Infect Dis 1999; 180: 278–84[Web of Science][Medline]
134. Gruters RA, Terpstra FG, De Goede RE et al. Immunological and virological markers in individuals progressing from seroconversion to AIDS. AIDS 1991; 5: 837–44[Web of Science][Medline]
135. Clerici M, Stocks NI, Zajac RA et al. Detection of three distinct patterns of T helper cell dysfunction in asymptomatic, human immunodeficiency virus-seropositive patients. Independence of CD4⁺ cell numbers and clinical staging. J Clin Invest 1989; 84: 1892–9[Web of Science][Medline]
136. Rosenberg ES, Billingsley JM, Caliendo A et al. Vigorous HIV-1-specific CD4⁺ T-cell responses associated with control of viraemia. Science 1997; 278: 1447–50[Abstract/Free Full Text]
137. Mellors JW, Kingsley LA, Rinaldo C et al. Quantitation of HIV-1 RNA in plasma predicts outcome after seroconversion. Ann Intern Med 1995; 122: 573–79[Abstract/Free Full Text]
138. Oxenius A, Price DA, Easterbrook PJ et al. Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8⁺ and CD4⁺ T lymphocytes. Proc Natl Acad Sci USA 2000; 97: 3382–7[Abstract/Free Full Text]
139. Levy JA. Caution: should we be treating HIV infection early? Lancet 1998; 352: 982–3[Web of Science][Medline]
140. Stranford SA, Ong JC, Martinez-Marino B et al. Reduction in CD8⁺ cell non-cytotoxic anti-HIV activity in individuals receiving highly active antiretroviral therapy during primary infection. Proc Natl Acad Sci USA 2001; 98: 597–602[Abstract/Free Full Text]
141. Rosenberg ES, Altfeld M, Poon SH et al. Immune control of HIV-1 after early treatment of acute infection. Nature 2000; 407: 523–6[Medline]

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