Characterization of HIV-1 Envelope V3 Region Sequences from Virologically Controlled HIV-Infected Older Patients on Long Term Antiretroviral Therapy

Abstract

Although many HIV-infected patients have attained older age owing to the success of antiretroviral therapy (ART) in controlling viremia and increasing CD4 T cell counts, HIV continues to persist in several target cells. We have characterized 514 HIV-1 envelope V3 region sequences (94-96 amino acids [aa]) from 25 HIVinfected older patients' peripheral blood mononuclear cell DNA on long-term ART with controlled viremia (undetectable viral load) and improved CD4 T cell counts. Phylogenetic analysis revealed that the V3 region sequences of each patient formed distinct clusters that were well separated and discriminated from other patients' sequences. The coding potential of the V3 region, including several patient-specific amino acid motifs and functional domains, including the two cysteines sandwiching the V3 loop, the central GPGR motif with variation at one position in some sequences, the base GDIR motif, and the N-glycosylation sites were generally conserved. The patients' V3 region sequences contained amino acid motifs conferring affinity mostly for CCR5 coreceptor, suggesting R5 phenotype. There was a low degree of heterogeneity and lower estimates of genetic diversity in all 25 patients' V3 region sequences. Twelve of 25 patients' V3 region sequences were found to be under positive selection pressure. Analysis of the several cytotoxic T lymphocytes (CTL) epitopes showed variation, whereas some of known neutralizing antibodies (nAbs) epitopes showed conservation in patients' V3 region sequences. In conclusion, a low degree of genetic variability and maintenance of functional domains with R5 phenotypes, and variation in CTL and conservation of nAb epitopes were the hallmarks of V3 region sequences from our 25 virologically controlled HIV-infected older patients on long-term ART.

Neutralization Sensitivity of HIV-1 CRF07_BC From an Untreated Patient With a Focus on Evolution Over Time

“…The slight fluctuation of genetic distance in the V3 region in our experiment confirmed that the conformational change of Env during virus assembly was inherently complex, as well as dynamic, on the cell surface ( Rossignol et al., 2021 ). The tetrapeptide of the V3 region is the binding site for the host to induce neutralizing antibodies and CTL reaction known to affect viral fusion and entry and determine the usage of co-receptors ( Bowder et al., 2018 ; Behrens et al., 2021 ). In the process of HIV-1 infection, the co-receptor mainly assists the virus to enter the cell.…”

“…Behrens et al. observed that a low degree of genetic variability and maintenance of functional domains with R5 phenotypes were the hallmarks of V3 region sequences from virologically controlled HIV-infected patients ( Behrens et al., 2021 ). All GPGQ of the tetrapeptides and CCR5-tropic viruses of our results were consistent with long-term non-progressive clinical characteristics of the subject.…”

Phenotypic frailty in people living with HIV is not correlated with age or immunosenescence

“…For this study we recruited patients who were compliant with ART, of an older age, virally suppressed for years, and who consented to cell harvesting for our studies of immunological aging. 11,13,14 Recruits were not chosen on the basis of frailty as that was measured later. It is important to note that frailty was determined within a year of cell surface analysis.…”

NanoHIV: A Bioinformatics Pipeline for Producing Accurate, Near Full-Length HIV Proviral Genomes Sequenced Using the Oxford Nanopore Technology

“…For instance, little is known about the correlation between immune escape variants amongst integrated, sequence-intact proviruses and circulating plasma viruses [14]. Generating long-read viral envelope sequences would also enable the assessment of viral diversity, cellular tropism and escape from neutralizing antibodies, especially in underrepresented populations with a high disease burden [15,16]. In addition, long sequence reads that include the variable loops of the envelope gene would provide sensitive detection of viral evolution and compartmentalization in central nervous system (CNS) and other tissues [17][18][19].…”