7 results found
Macharia GN, Yue L, Staller E, et al., 2020, Infection with multiple HIV-1 founder variants is associated with lower viral replicative capacity, faster CD4(+)T cell decline and increased immune activation during acute infection, PLoS Pathogens, Vol: 16, Pages: 1-22, ISSN: 1553-7366
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 pr
El-Badry E, Macharia G, Claiborne D, et al., 2020, Better Viral Control despite Higher CD4(+) T Cell Activation during Acute HIV-1 Infection in Zambian Women Is Linked to the Sex Hormone Estradiol, JOURNAL OF VIROLOGY, Vol: 94, ISSN: 0022-538X
Claiborne DT, Scully EP, Palmer CD, et al., 2019, Protective HLA alleles are associated with reduced LPS levels in acute HIV infection with implications for immune activation and pathogenesis, PLOS PATHOGENS, Vol: 15, ISSN: 1553-7366
Macharia G, Staller E, Yue L, et al., 2018, Infection With Multiple Transmitted/Founder (TF) HIV-1 Viruses Impacts Peak VL and HIV-1 Pathogenesis, HIV Research for Prevention 2018: AIDS Vaccine, Microbicide and ARV-based Prevention Science (HIVR4P)
Muema DM, Macharia GN, Olusola BA, et al., 2017, Proportions of circulating follicular helper T cells are reduced and correlate with memory B cells in HIV-infected children, PLOS ONE, Vol: 12, Pages: e0175570-e0175570
Muema DM, Macharia GN, Hassan AS, et al., 2015, Control of Viremia Enables Acquisition of Resting Memory B Cells with Age and Normalization of Activated B Cell Phenotypes in HIV-Infected Children, The Journal of Immunology, Vol: 195, Pages: 1082-1091, ISSN: 0022-1767
Claiborne DT, Prince JL, Scully E, et al., 2015, Replicative fitness of transmitted HIV-1 drives acute immune activation, proviral load in memory CD4+ T cells, and disease progression, Proc Natl Acad Sci U S A, ISSN: 1091-6490
HIV-1 infection is characterized by varying degrees of chronic immune activation and disruption of T-cell homeostasis, which impact the rate of disease progression. A deeper understanding of the factors that influence HIV-1-induced immunopathology and subsequent CD4+ T-cell decline is critical to strategies aimed at controlling or eliminating the virus. In an analysis of 127 acutely infected Zambians, we demonstrate a dramatic and early impact of viral replicative capacity (vRC) on HIV-1 immunopathogenesis that is independent of viral load (VL). Individuals infected with high-RC viruses exhibit a distinct inflammatory cytokine profile as well as significantly elevated T-cell activation, proliferation, and CD8+ T-cell exhaustion, during the earliest months of infection. Moreover, the vRC of the transmitted virus is positively correlated with the magnitude of viral burden in naive and central memory CD4+ T-cell populations, raising the possibility that transmitted viral phenotypes may influence the size of the initial latent viral reservoir. Taken together, these findings support an unprecedented role for the replicative fitness of the founder virus, independent of host protective genes and VL, in influencing multiple facets of HIV-1-related immunopathology, and that a greater focus on this parameter could provide novel approaches to clinical interventions.
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