Cumulative Impact of Host and Viral Factors on HIV-1 Viral-Load Control during Early Infection

Abstract

fIn HIV-1 infection, the early set-point viral load strongly predicts both viral transmission and disease progression. The factors responsible for the wide spectrum of set-point viral loads are complex and likely reflect an interplay between the transmitted virus and genetically defined factors in both the transmitting source partner and the seroconverter. Indeed, analysis of 195 transmission pairs from Lusaka, Zambia, revealed that the viral loads in transmitting source partners contributed only ϳ2% of the variance in early set-point viral loads of seroconverters (P ‫؍‬ 0.046 by univariable analysis). In multivariable models, early setpoint viral loads in seroconverting partners were a complex function of (i) the viral load in the source partner, (ii) the gender of the seroconverter, (iii) specific HLA class I alleles in the newly infected partner, and (iv) sharing of HLA-I alleles between partners in a transmission pair. Each of these factors significantly and independently contributed to the set-point viral load in the newly infected partner, accounting for up to 37% of the variance observed and suggesting that many factors operate in concert to define the early virological phenotype in HIV-1 infection. The HIV-1 set-point viral load (VL) in infected individuals directly affects the transmission rate of the virus (1-3) and early disease progression (4-6). Recent studies have shown a trend of increasing set-point VLs over the last 30 years of the HIV-1 epidemic (7, 8), raising the possibility of both increasing transmission rates and virulence in treatment of naïve HIV-1 infection. A plausible explanation for this observation is viral adaptation to the host at the population level over time (9, 10), providing a further challenge for HIV-1 vaccine design. The determinants of set-point VL in newly infected individuals include viral genetic factors (11-13) and host genetic factors (14-16). Thus, to comprehensively define the role of underlying factors in determining early set-point VL, it is necessary to understand the complexity of the interaction between the transmitted founder virus, with its embedded footprints of the immune response of the transmitting source partner (TSP), and the de novo immune defense of the seroconverting partner (SC).We previously observed that cytotoxic T-lymphocyte (CTL) epitope escape mutations selected by immune pressure in the TSP can modulate the early set-point VL in the SC (11, 17), suggesting that mutations that would be expected to positively impact VL in the TSP can negatively impact VL in the seroconverter. This observation is consistent with our previous studies of the ZEHRP cohort and with other studies of heterosexual cohorts of limited size. These studies demonstrated a relatively weak correlation between VLs in TSPs and SCs in linked heterosexual transmission partners (18)(19)(20). In contrast, a more significant VL correlation was shown for a transmission pair cohort of men who have sex with men (MSM) in San Francisco (21), and a phylogenetic analysis of MSM in the Swi...

Population-Level Immune-Mediated Adaptation in HIV-1 Polymerase during the North American Epidemic

“…Analogous to the negative effects of transmitted drug resistance on treatment efficacy (23), acquisition of HIV-1 "preadapted" to (i.e., harboring escape mutations specific for) an individual's HLA alleles could compromise cellular immune responses to the incoming virus. This is supported by the observation that individuals infected with HIV-1 harboring polymorphisms associated with HLA alleles they share with their donors (their mothers in the case of vertical trans-mission or partners in the case of horizontal transmission) display suboptimal CTL responses and/or adverse clinical outcomes (19,(24)(25)(26)(27).…”

Replicative fitness of transmitted HIV-1 drives acute immune activation, proviral load in memory CD4 + T cells, and disease progression

“…Previously, our work, and that of others, showed that transmitted viral characteristics significantly correlate with early SPVL (11,13,14) as well as CD4 + T-cell decline up to 3 y postinfection (15). Here, we sought to determine the underlying mechanisms by which vRC of transmitted HIV-1 impacts the trajectory of CD4 decline even in the context of viral control by previously identified host factors, such as protective HLA alleles, that also impact disease progression.…”

“…The observation that not all individuals harboring such protective HLA class I alleles go on to become long-term nonprogressors suggests that other factors outside of host immunogenetics play a role in defining disease progression (12). Transmitted viral characteristics have been shown to impact viral load within heterosexual transmission pairs, suggesting that viral characteristics are heritable and can impact disease severity (11,13,14). Moreover, we recently showed that attenuated viral replicative capacity (vRC) of the transmitted virus, defined in vitro by the Gag sequence, was associated with a significant delay in CD4 + T-cell decline in individuals recently infected with HIV-1 subtype C (15).…”

Host Genetic and Viral Determinants of HIV-1 RNA Set Point among HIV-1 Seroconverters from Sub-Saharan Africa

“…Additionally, in this model, HLA concordance within transmission pairs and TLR SNPs of the seroconverter also were associated with changes in set point. In a previous study of Zambian HIV-1 serodiscordant couples, male sex, age, HLA alleles, HLA concordance, and source partner HIV-1 RNA level explained ϳ37% of the variation in set point (9). The increased variation explained by our current model may be partly attributed to variation in the TLR genes, which previously have been shown to be associated with innate host control of HIV-1 (30, 32-39).…”

“…This HIV-1 set point level is a critical determinant of later disease progression and infectivity (1)(2)(3)(4) and is thought to be a measure of the balance between the replicative fitness of the transmitted virus and the antiviral responses of the new host. The importance of viral characteristics in determining set point is supported by multiple studies reporting a strong correlation between plasma HIV-1 RNA levels in HIV-1-transmitting (source) partners with the HIV-1 set point of their seroconverting partner (5)(6)(7)(8)(9)(10). The host contribution is exemplified by the importance of variation in the human leukocyte antigen (HLA) class I (HLA-A, HLA-B, and HLA-C) genes, which are strongly associated with set point by virtue of the essential role for HLA in presenting HIV-1 peptides to CD8 ϩ T cells (11).…”