HIV RNA levels in transmission sources only weakly predict plasma viral load in recipients

In a typical HIV-1-infected patient, plasma viral load (pVL) increases steeply in the first week after acute infection, then decreases as the immune system becomes activated, resulting in antibody seroconversion 3–13 days after infection and a full western blot pattern approximately 3 months later [1–3]. The so-called viral set point or steady-state viral load is reached after approximately 40–276 days from the acute infection moment [1]. Especially in the first few weeks of infection, differences are obvious in patients, especially with regard to time to peak load and time to viral load drop from peak to nadir [1], but also in the absolute viral RNA count. The viral set point is thought to represent a trade-off between viral replication capacity and repression of the virus by the host immune system. HIV-1 RNA levels vary considerably between individuals and also throughout the infection course in a particular individual. The viral load at set point is an important parameter, as it is strongly predictive of clinical progression [4,5]. Both the innate replicating capacity (fitness) of the virus strain and the strength of the host immune system would intuitively be the most obvious contributors, but it has been suggested that age, sex, shared human leukocyte antigen (HLA) alleles and duration of infection also contribute to the phenomenon [6]. The involvement of virus characteristics could easily be measured by analyzing the HIV replication capacity in donor–recipient pairs, wherein the viral load should be similar if viral replication fitness is the main determinant of pVL. A cohort of transmission pairs, necessary to study comparative HIV-1 viral load dynamics, is not easy to establish. Viral relationships indicative of transmission should first be determined by phylogenetic analysis. Then, an acute phase plasma sample (to minimize the effect of immune pressure) of the recipient and a matching sample from the donor should be available. Hecht et al. [7] have analyzed early plasma samples from 24 such transmission pairs, all comprising men having sex with men (MSM), and reported a significant correlation between the HIV-1 RNA levels within the transmission pairs. However, they cautioned that these results should be reproduced in other cohorts to validate the finding. We here report a similar analysis in early samples from 56 sequence-verified HIV-1 transmission pairs, 60% MSM and 40% heterosexual, from The Netherlands. Recipients were sampled during primary infection, 20 recipients were in Fiebig et al. [8] stages III–IV (viral RNA+/− or indeterminate western blot) and 36 recipients were in Fiebig et al. [8] stages V (viral RNA+/western blot p31−) and VI (viral RNA+/western blot fully developed). HIV-1 blood pVL measurements were done using the Versant HIV-1 RNA 3.0 assay (Bayer Diagnostics Division, Tarrytown, New York, USA), NucliSens HIV-1 RNA (bioMérieux, Boxtel, The Netherlands) or m2000rt (Abbott Molecular Inc., Des Plaines, Illinois, USA). Viral loads of all couples were measured using the same assay. Samples from donors matched the time point when recipient samples were taken. Linear regression analysis was done with GraphPad Prism, version 5.01 (GraphPad Software, San Diego, California, USA) and correlation coefficients were calculated. In contrast to Hecht et al. [7], we do not find a strong correlation between plasma viral RNA levels within the pairs (Fig. 1). The Pearson coefficient of correlation (r) in our cohort was 0.25 for all 56 transmission pairs, 0.29 (range −0.17 to 0.65) for pairs when the recipients were in Fiebig et al. [8] stages III–IV and 0.06 (range −0.27 to 0.39) for pairs when the recipients were in Fiebig et al. [8] stages V–VI, suggesting that the correlation is completely lost when the infection progresses. The correlation coefficient (r) between viral RNA levels in donors and recipients was 0.55 in the 24 pairs studied by Hecht et al. [7], which were in similar early stages of HIV infection. A correlation coefficient (r) above 0.8 is usually denoted as strong and below 0.5 as weak, whereas r is equal to 1 represents a perfect correlation. So, in our transmission pairs, we detect only a weak correlation between viral RNA levels in acutely infected recipients and donors. Similar results were obtained for a transmission cohort [6] in Zambia where the viral RNA levels between 115 donor and seroconverting recipient pairs had a correlation coefficient (r) of 0.21 (P = 0.03). In this study, factors such as sex, age, HLA markers and duration of infection were also shown to contribute.Fig. 1: Relationship of HIV-1 RNA levels in 56 transmission pairs. Viral RNA levels in blood plasma from source individuals were correlated with viral RNA levels in recipients in the acute or early stages of infection. Correlations are shown for all 56 transmission pairs or for sources and recipients when the latter are separated according to the primary infection stage criteria of Fiebig et al. [8].The low correlation between pVL in donors and recipients suggests that viral traits do contribute to pVL early in infection, but that other factors are equally or more important.