Influence of Gag-Protease-Mediated Replication Capacity on Disease Progression in Individuals Recently Infected with HIV-1 Subtype C

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f Human immunodeficiency virus type 1 (HIV-1) evolves rapidly in response to host immune selection pressures. As a result, the functional properties of HIV-1 isolates from earlier in the epidemic may differ from those of isolates from later stages. However, few studies have investigated alterations in viral replication capacity (RC) over the epidemic. In the present study, we compare Gag-Protease-associated RC between early and late isolates in Japan (1994 to 2009). HIV-1 subtype B sequences from 156 antiretroviral-naïve Japanese with chronic asymptomatic infection were used to construct a chimeric NL4-3 strain encoding plasmaderived gag-protease. Viral replication capacity was examined by infecting a long terminal repeat-driven green fluorescent protein-reporter T cell line. We observed a reduction in the RC of chimeric NL4-3 over the epidemic, which remained significant after adjusting for the CD4 ؉ T cell count and plasma virus load. The same outcome was seen when limiting the analysis to a single large cluster of related sequences, indicating that our results are not due to shifts in the molecular epidemiology of the epidemic in Japan. Moreover, the change in RC was independent of genetic distance between patient-derived sequences and wildtype NL4-3, thus ruling out potential temporal bias due to genetic similarity between patient and historic viral backbone sequences. Collectively, these data indicate that Gag-Protease-associated HIV-1 replication capacity has decreased over the epidemic in Japan. Larger studies from multiple geographical regions will be required to confirm this phenomenon.

Section: No Significant Temporal Changes In Cd4mentioning

confidence: 99%

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confidence: 99%

Significant Reductions in Gag-Protease-Mediated HIV-1 Replication Capacity during the Course of the Epidemic in Japan

Nomura

Hosoya

Brumme

et al. 2013

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“…This effect was more flagrant with inserts from acutely compared to chronically infected subjects and has been attributed in part to the presence of HLA-associated polymorphisms in controllers and the development of compensatory mutations that restore fitness over time (15,20). These studies were performed using a subject-derived gene integrated in a common HIV-1 backbone (9,(15)(16)(17)(18)(19)(20)(21)(22)(23)(24), and thus the results are contingent on mutations that are private to each subject's viruses and the replicative capacity of these viruses reflect a combination of mutations that differs from one subject to the next. More recently, infectious molecular clones have been developed from a number of subjects (25)(26)(27)(28)(29) and these infectious molecular clones provide the best opportunity to study interactions between different mutations and subject-specific mutational pathways that are evidenced during an HIV-1 infection.…”

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confidence: 99%

HIV-1 Conserved-Element Vaccines: Relationship between Sequence Conservation and Replicative Capacity

Rolland

Manocheewa

Swain

et al. 2013

bTo overcome the problem of HIV-1 variability, candidate vaccine antigens have been designed to be composed of conserved elements of the HIV-1 proteome. Such candidate vaccines could be improved with a better understanding of both HIV-1 evolutionary constraints and the fitness cost of specific mutations. We evaluated the in vitro fitness cost of 23 mutations engineered in the HIV-1 subtype B Gag-p24 Center-of-Tree (COT) protein through fitness competition assays. While some mutations at conserved sites exacted a high fitness cost, as expected under the assumption that the most conserved residue confers the highest fitness, there was no overall strong relationship between sequence conservation and replicative capacity. By comparing sites that have evolved since the beginning of the epidemic to those that have remain unchanged, we found that sites that have evolved over time were more likely to correspond to HLA-associated sites and that their mutation had limited fitness costs. Our data showed no transcendent link between high conservation and high fitness cost, indicating that merely focusing on conserved segments of HIV-1 would not be sufficient for a successful vaccine strategy. Nonetheless, a subset of sites exacted a high fitness cost upon mutation-these sites have been under selective pressure to change since the beginning of the epidemic but have proved virtually nonmutable and could constitute preferred targets for vaccine design.

“…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)(12)(13) and host genetic factors (14)(15)(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).…”

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confidence: 99%

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

Yue

Prentice

Farmer

et al. 2013

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...