Abstract
HIV-1 transmission is associated with a severe bottleneck in which a limited number of variants from a pool of genetically diverse quasispecies establishes infection. The IAVI protocol C cohort of discordant couples, female sex workers, other heterosexuals and men who have sex with men (MSM) present varying risks of HIV infection, diverse HIV-1 subtypes and represent a unique opportunity to characterize transmitted/founder viruses (TF) where disease outcome is known. To identify the TF, the HIV-1 repertoire of 38 MSM participants' samples was sequenced close to transmission (median 21 days post infection, IQR 18-41) and assessment of multivariant infection done. Patient derived gag genes were cloned into an NL4.3 provirus to generate chimeric viruses which were characterized for replicative capacity (RC). Finally, an evaluation of how the TF virus predicted disease progression and modified the immune response at both acute and chronic HIV-1 infection was done. There was higher prevalence of multivariant infection compared with previously described heterosexual cohorts. A link was identified between multivariant infection and replicative capacity conferred by gag, whereby TF gag tended to be of lower replicative capacity in multivariant infection (p = 0.02) suggesting an overall lowering of fitness requirements during infection with multiple variants. Notwithstanding, multivariant infection was associated with rapid CD4+ T cell decline and perturbances in the CD4+ T cell and B cell compartments compared to single variant infection, which were reversible upon control of viremia. Strategies aimed at identifying and mitigating multivariant infection could contribute toward improving HIV-1 prognosis and this may involve strategies that tighten the stringency of the transmission bottleneck such as treatment of STI. Furthermore, the sequences and chimeric viruses help with TF based experimental vaccine immunogen design and can be used in functional assays to probe effective immune responses against TF.
Highlights
HIV infection is considered a life-long illness that remains a chronic disease manageable only by successfully suppressive combination antiretroviral therapy but for which no cure or vaccines are available [1]
We observed a higher frequency of multivariant infection in men who have sex with men (MSM) than has been previously described in heterosexually infected participants, and this was associated with faster decline of CD4+ T cells and perturbances in the CD4+ T cell and the B cell compartment
The replicative capacity conferred by gag was lower in multivariant infection, suggesting a less stringent transmission bottleneck that allowed for less fit variants to establish infection
Summary
HIV infection is considered a life-long illness that remains a chronic disease manageable only by successfully suppressive combination antiretroviral therapy (cART) but for which no cure or vaccines are available [1]. In order to inform the rational design of new interventions it is critical to understand the complex and dynamic events occurring during acute HIV-1 infection which set the stage for disease trajectory. The outcome of these early events is shaped by both the virus characteristics and multiple host factors which when favorably aligned result in initial control of viremia and preservation of CD4+ T cell counts, albeit to different levels in different patients [2,3,4]. Variations in disease progression have been reported despite the presence of favorable host genetic factors including HLA types that are associated with viral control, underscoring the importance of viral characteristics in influencing disease trajectory [5, 6]
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