Genetic and Functional Analysis of HIV Type 1nefGene Derived from Long-Term Nonprogressor Children: Association of Attenuated Variants with Slow Progression to Pediatric AIDS

Abstract

Among persons infected by HIV-1, the rate of progression to AIDS is multifactorial being affected by host and viral factors, including the HIV-encoded negative factor (Nef). Our aim was to define whether variations in the nef gene as well as its functions may be associated with slower HIV disease course in infected children. The proviral HIV-1 nef gene was cloned, sequenced, and compared in children with contrasting disease course: 10 long-term nonprogressors (LTNP) and six rapid progressor (RP). The CD4 and MHC-I down-modulation ability of nef alleles derived from LTNP and RP children was analyzed. We observed that only one of our 10 LTNP had a protective genetic background, and out of them, 40% had defective nef genes, carrying substitutions at the (AWLEAQ(56-61)) and the (Rxx(22-24)) domains, and that those alleles were unable of down-regulate CD4 and MHC-I. The emergence or presence of Nef L58V substitution was associated with viral attenuation, indicated by a reduction in HIV viral loads, a persistent preservation of CD4(+) T cell counts, and lack of AIDS-related symptoms. Our results demonstrate that HIV-1 perinatally infected children carrying functionally defective nef HIV-1 strains have prolonged asymptomatic phases without therapy, suggesting a relevant role of CD4 and MHC-I down-modulation Nef domains on in vivo HIV-1 pathogenesis and pediatric immunodeficiency outcome.

No Evidence for Selection of HIV-1 with Enhanced Gag-Protease or Nef Function among Breakthrough Infections in the CAPRISA 004 Tenofovir Microbicide Trial

“…Other groups have reported conflicting associations between Nef-mediated CD4 or HLA downregulation function and clinical markers of disease [7], [9], [16], [17]; however, we observed no association between these factors in our study.…”

“…However, it remains important to ensure that antiretroviral-based strategies for HIV prophylaxis do not introduce sieving effects [3] or result in the selection of viral variants with enhanced fitness or pathogenesis in individuals with breakthrough infection. The functional characteristics of an individual's virus can influence the disease course [4], [5], [6], [7], [8], [9], [10], [11]; as such, inadvertent selection of fitter HIV-1 strains at or shortly after transmission may have clinical implications.…”

“…Building on previous studies that demonstrated substantial inter-individual differences in gag-protease replication capacity [4], [10] and nef function [7], [9], we investigated whether tenofovir gel prophylaxis was associated with differences in the in vitro function of early/transmitted viral Gag-Protease and Nef proteins.…”

A robust and scalable TCR-based reporter cell assay to measure HIV-1 Nef-mediated T cell immune evasion

“…In particular, Nef's ability to downregulate HLA-I molecules, specifically HLA-A and -B alleles, reduces CTL recognition and killing of virusinfected cells (Adnan et al, 2006;Collins et al, 1998;Yang et al, 2002). Deletions or mutations in Nef have been identified in HIV-1 long-term non-progressors (Corró et al, 2012;Deacon et al, 1995;Kirchhoff et al, 1995;Learmont et al, 1999) and Nef alleles isolated from elite controllers have decreased in vitro ability to downregulate HLA-I compared to those from progressors , indicating that Nef contributes significantly to disease outcome. As such, novel inhibitors of Nef are expected to be of clinical benefit.…”

Pediatric HIV Long-Term Nonprogressors

“…These etiologies consist of gene and receptor mutations [3], various mitochondrial DNA types [4], and different human leukocyte antigen (HLA) types, specifically HLA-B27 or HLA-B57 [5]. Perinatally infected children with HIV may acquire the same genes and HLA as their mothers.…”