HIV-1 transmission is associated with a severe bottleneck in which a limited number of variants from genetically diverse quasispecies establish 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 present a unique opportunity to characterize transmitted/founder viruses (TFv) where disease outcome is known.
To identify the TFv, the HIV-1 repertoire of 38 MSM was sequenced close to transmission (median
21dpi) and assessment of multivariant infection, subtype and genetic polymorphisms done. Patient derived gag genes were cloned into a NL4.3 provirus to generate chimeric viruses which were characterised for replicative capacity (RC) and mechanism of spread between cells. Finally, an evaluation of how the virus characteristics that were predictors of disease progression modified the immune response at both acute and chronic HIV-1 infection was done.
There was higher incidence of multivariant infection compared with previously described heterosexual cohorts. TFv predictors of CD4 T-cell decline and set-point viral load included multivariant infection, subtype, drug resistance mutations and RC. A link was identified between these characteristics and both chronic immune activation and rapid CD4+ T cell decline except in multivariant infection where perturbations were restored after control of viremia. The cell entry and CD4+ T cell depletion mechanisms by high RC TFv overlapped with those involved in cell-cell transmission but not cell free spread and involved increased expression of RNA that encodes proteins involved in apoptosis,
autophagy and necrosis. Strategies aimed at mitigating persistent immune activation could contribute toward improving HIV-1 prognosis and research presented in this thesis suggests that this may involve strategies that sieve out
high RC TFv and tighten the stringency of the transmission bottleneck. Furthermore, the sequences and chimeric viruses provide a useful resource in the field of immunogen design, for their utility in designing TFv peptide sets and for use in functional assays to probe effective immune responses against TFv.