Transmitted/Founder HIV-1 Subtype C Viruses Show Distinctive Signature Patterns in Vif, Vpr, and Vpu That Are Under Subsequent Immune Pressure During Early Infection

Abstract

Viral variants that predominate during early infection may exhibit constrained diversity compared with those found during chronic infection and could contain amino acid signature patterns that may enhance transmission, establish productive infection, and influence early events that modulate the infection course. We compared amino acid distributions in 17 patients recently infected with HIV-1C with patients with chronic infection. We found significantly lower entropy in inferred transmitted/founder (t/f) compared with chronic viruses and identified signature patterns in Vif and Vpr from inferred t/f viruses. We investigated sequence evolution longitudinally up to 500 days postseroconversion and compared the impact of selected substitutions on predicted human leukocyte antigen (HLA) binding affinities of published and predicted cytotoxic T-lymphocyte epitopes. Polymorphisms in Vif and Vpr during early infection occurred more frequently at epitope-HLA anchor residues and significantly decreased predicted epitope-HLA binding. Transmission-associated sequence signatures may have implications for novel strategies to prevent HIV-1 transmission.

HIV-1 Vpr antagonizes innate immune activation by targeting karyopherin-mediated NF-κB/IRF3 nuclear transport

“…A link between escape from innate sensing and successful transmission is suggested by several lines of evidence. These include a generally low HIV transmission frequency (Shaw & Hunter, 2012), the observation that HIV transmitted founder clones are particularly resistant to IFN (Iyer et al, 2017), and encode distinct Vpr amino acid signatures, as compared to chronic viruses (Rossenkhan et al, 2016), as well as the HIV transmission-associated cytokine storm itself (Stacey et al, 2009). Concordantly, Vpu, Nef and Vif, and Vpr, antagonize innate immunity to enhance viral replication, reviewed in Sumner et al, 2019. Vpr has been suggested to cause IRF3 degradation (Okumura et al, 2008) but we did not detect IRF3 degradation in THP-1 cells under conditions when gene expression and IRF3 nuclear transport were strongly suppressed ( Figure 5).…”

The influence of viral protein R amino acid substitutions on clinical outcomes in people living with HIV: A systematic review

“…Note: Longitudinal studies. 51,[64][65][66][67]74,76,78 Cross-sectional studies. 49,52,63,[70][71][72][73]75,77,79,[80][81][82]84 Case studies.…”

“…The amino acid substitutions 2E, 18W, 29G, 31D, 33H, 41G, 44R, 55A, 63T, 65R, 70I, 70V, 76C, 77Q, 78H, 83V, 85P, 86G, 86R, 89G, 89T, 89S, 89A, 93A, 93S, 93R and 94G were associated with positive clinical outcomes (Table 1 and Figure 4A). In particular, these Vpr amino acid substitutions were more prevalent with long-term nonprogressors (LTNP), 64,67,[70][71][72][73][74] lower viral load 75 and higher CD4 + count 75,76 (Table 1). The amino acid substitutions 3R, 21I, 22L, 41S, 64P, 75R, 77Q and 79G were associated with negative clinical outcomes (Table 1) and were more prevalent with progressors and/or acute HIV-1 infection, 63,67,74 higher viral load 66 and lower CD4 + count 66 (Table 1).…”

“…In particular, these Vpr amino acid substitutions were more prevalent with long-term nonprogressors (LTNP), 64,67,[70][71][72][73][74] lower viral load 75 and higher CD4 + count 75,76 (Table 1). The amino acid substitutions 3R, 21I, 22L, 41S, 64P, 75R, 77Q and 79G were associated with negative clinical outcomes (Table 1) and were more prevalent with progressors and/or acute HIV-1 infection, 63,67,74 higher viral load 66 and lower CD4 + count 66 (Table 1). The amino acid substitutions 17E, 20L, 21E, 22L, 23L, 24E, 25E, 26L, 29E, 30A, 35P, 54W, 73R, 77Q, 77H, 80R, 85P and 87P were associated with no significant contribution to disease progression 51,65,73,[77][78][79][80] (Table 1).…”

Targeting Uracil-DNA Glycosylases for Therapeutic Outcomes Using Insights from Virus Evolution

“…Any general Vpr-inhibiting compounds making it into the clinic would have the potential to compromise HIV-1 viability fairly comprehensively [102]. It should be noted that Vpr, in common with other accessory proteins, is under selective pressure following initial infection and [presumably active] variants are easy to find in the databases ( Figure 5) [103]. As will be explored next, UNG2 and its essential PPIs in HIV-1 maturation, are of parallel interest as potential targets for antiretroviral therapy.…”