A number of genetic and immunological factors have been linked to an individual’s ability to control HIV replication after acquiring infection. The contribution of properties of the virus has been less clear, although certain subtypes of HIV have been associated with faster disease progression (specifically subtype D). Two recent studies have attempted to shed light on this issue by studying viral load levels among couples where there was strong evidence that one partner transmitted HIV to the other. One study was conducted in heterosexual couples in Rakai, Uganda, while the other involved gay men in San Francisco, USA. In both studies, there was a statistically significant association between the viral load level in the person who transmitted and the set point viral load level in the partner who acquired the infection.
The researchers conclude that there are likely intrinsic viral factors that contribute to the viral load level; in the larger of the two studies it is estimated that these factors contribute approximately 16-37% of the variance in viral load between different individuals. Both papers note that an alternative explanation of the findings might be that viral load is linked to the relative dose of virus that an individual is exposed to (which would likely be higher if the transmitting partner has a high viral load); however, studies in the SIV model have not found evidence of a significant link between the dose of virus animals are challenged with and the set point viral load.
Although the findings of these two independent studies are compelling, it must also be borne in mind that chronically infected individuals harbor a diverse population of HIV variants and very recent evidence suggests that the specific variant that is transmitted can influence the outcome of infection in the newly infected person. This evidence was reported at the Keystone HIV vaccines meeting last month, where a team of researchers from the UK documented a case where an HIV-infected individual transmitted to two different people on the same night, with divergent outcomes (see abstract appended below).
PLoS Pathog 6(5): e1000876. doi:10.1371/journal.ppat.1000876
HIV-1 Transmitting Couples Have Similar Viral Load Set-Points in Rakai, Uganda
T. Déirdre Hollingsworth1, Oliver Laeyendecker2,3, George Shirreff1, Christl A. Donnelly1, David Serwadda4,5, Maria J. Wawer5,6, Noah Kiwanuka4,5, Fred Nalugoda5, Aleisha Collinson-Streng3, Victor Ssempijja5, William P. Hanage7, Thomas C. Quinn2,3, Ronald H. Gray5,6, Christophe Fraser1*
1 MRC Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom, 2 School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America, 3 National Institute of Allergy and Infectious Diseases, National Institutes of Health, Baltimore, Maryland, United States of America, 4 School of Public Health, Makerere University, Kampala, Uganda, 5 Rakai Health Science Program, Entebbe, Uganda, 6 Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America, 7 Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom
Abstract
It has been hypothesized that HIV-1 viral load set-point is a surrogate measure of HIV-1 viral virulence, and that it may be subject to natural selection in the human host population. A key test of this hypothesis is whether viral load set-points are correlated between transmitting individuals and those acquiring infection. We retrospectively identified 112 heterosexual HIV-discordant couples enrolled in a cohort in Rakai, Uganda, in which HIV transmission was suspected and viral load set-point was established. In addition, sequence data was available to establish transmission by genetic linkage for 57 of these couples. Sex, age, viral subtype, index partner, and self-reported genital ulcer disease status (GUD) were known. Using ANOVA, we estimated the proportion of variance in viral load set-points which was explained by the similarity within couples (the ‘couple effect’). Individuals with suspected intra-couple transmission (97 couples) had similar viral load set-points (p = 0.054 single factor model, p = 0.0057 adjusted) and the couple effect explained 16% of variance in viral loads (23% adjusted). The analysis was repeated for a subset of 29 couples with strong genetic support for transmission. The couple effect was the major determinant of viral load set-point (p = 0.067 single factor, and p = 0.036 adjusted) and the size of the effect was 27% (37% adjusted). Individuals within epidemiologically linked couples with genetic support for transmission had similar viral load set-points. The most parsimonious explanation is that this is due to shared characteristics of the transmitted virus, a finding which sheds light on both the role of viral factors in HIV-1 pathogenesis and on the evolution of the virus.
AIDS: 24 April 2010 - Volume 24 - Issue 7 - p 941–945
doi: 10.1097/QAD.0b013e328337b12e
Basic Science
HIV RNA level in early infection is predicted by viral load in the transmission source
Hecht, Frederick M; Hartogensis, Wendy; Bragg, Larry; Bacchetti, Peter; Atchison, Robert; Grant, Robert; Barbour, Jason; Deeks, Steven G
Abstract
Objective: HIV-1 viral load in early infection predicts the risk of subsequent disease progression but the factors responsible for the differences between individuals in viral load during this period have not been fully identified. We sought to determine the relationship between HIV-1 RNA levels in the source partner and recently infected recipient partners within transmission pairs.
Methods: We recruited donor partners of persons who presented with acute or recent (<6 months) HIV infection. Transmission was confirmed by phylogenetic comparison of virus sequence in the donor and recipient partners. We compared viral load in the donor partner and the recipient in the first 6 months of HIV infection.
Results: We identified 24 transmission pairs. The median estimated time from infection to evaluation in acutely/recently infected recipient individuals was 72 days. The viral load in the donor was closely associated with viral load at presentation in the recipient case (r = 0.55, P = 0.006).
Conclusion: The strong correlation between HIV-1 RNA levels within HIV transmission pairs indicates that virus characteristics are an important determinant of viral load in early HIV infection.
Keystone Symposia: HIV Vaccines (X5), March 21-26, 2010, Banff, Alberta, Canada
ABSTRACT NUMBER: 144
Sexual transmission of highly-distinct HIV-1 variants from a single donor to two recipients on the same night: divergent immune recognition and clinical outcomes
Suzanne English1*, David Bonsall2*, Aris Katzourakis, Peter Flanagan, Anna Duda, Sara Fidler, Jonathan Weber, Myra McClure, Rodney Phillips, John Frater and the SPARTAC trial investigators. 1. Nuffield Department of Clinical Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, South Parks Road, Oxford, OX1 3SY, UK. 2. Faculty of Medicine, Imperial College London, St. Mary’s Campus, Norfolk Place, London W2 1PG, UK. *Contributed equally.
It is important for vaccine development to understand why a particular variant is transmitted and how it impacts on clinical progression. Here we report a highly unusual case of two MSM (P1 and P2) infected with HIV-1 clade B by a third party on the same night, and their different clinical progression, Samples were taken at 71 days post-infection (baseline). P1 and P2 were treatment naïve. No donor sample was available.
Although phylogenetics supported a single donor (baseline gag inter-host distance 1%, env and gag bootstrap 100%), remarkably different viruses were transmitted to the two recipients; single genome amplification env sequences from P1 and P2 were separated by a distance equivalent to at least 3.6 years of within-host evolution prior to transmission (intra-host vs inter-host distance 0.68% within P1 and P2 vs 6.4%).
Viral load was lower in P1 than P2 (5.0 x105 vs 1.0 x106 copies/ml) and CD4+ higher (570 vs 280 cells ml). This was associated with broader gag-directed CD8+ ELISpot response in P1 than P2 (3 peptides vs 1 peptide) and a narrower env response (0 vs 2 peptides).
Viruses pseudotyped with env derived from P1 were 5 times more infectious in vitro than P2. This correlated with fewer potential N-linked glycosylation sites in gp120 (average 24 vs 28) and longer V1V2 length (average 88 vs 84 aa). There was no autologous or heterologous neutralizing antibody activity (IC50<20).
HIV-1 preventative vaccine development must consider that very different viruses can be transmitted from a single donor, with divergent infectivity, immune recognition and disease progression.
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