Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 May 29;92(12):e00346-18.
doi: 10.1128/JVI.00346-18. Print 2018 Jun 15.

Control of HIV-1 Pathogenesis in Viremic Nonprogressors Is Independent of Gag-Specific Cytotoxic T Lymphocyte Responses

Affiliations

Control of HIV-1 Pathogenesis in Viremic Nonprogressors Is Independent of Gag-Specific Cytotoxic T Lymphocyte Responses

Maria Salgado et al. J Virol. .

Abstract

Viremic nonprogressors (VNPs) constitute a very scarce group of untreated human immunodeficiency virus type 1 (HIV-1)-infected individuals who maintain stable CD4+ T cell counts despite high levels of HIV-1 replication. The specific factors associated with this atypical control of the HIV infection have been poorly described. Since specific T cell responses seem to be one of the main causes of HIV-1 control in elite controllers, we studied whether HIV-1 Gag-specific cytotoxic T lymphocyte (CTL) responses could also modulate disease control in VNPs. We characterized the immune responses from four VNPs compared to those of five standard progressors (SPs) during the first years of HIV-1 infection. We observed no differences in the breadth and frequency of Gag-specific cellular responses. Furthermore, we obtained 217 HIV-1Gag clonal sequences in which the viral variability of Gag increased over 3 years of infection for synonymous and nonsynonymous mutations in both VNPs and SPs. VNPs evolution rates in gag were comparable to SPs. This observation is in line with a similar accumulation of CTL putative escape mutations in Gag epitopes targeted by CTL responses. Altogether, the absence of viral pathogenesis in VNP individuals seems to be independent of HIV-Gag-specific CTL responses. This novel information guides to the study of alternative mechanism of HIV-1 pathogenesis control.IMPORTANCE Control of HIV infection has been widely studied in elite controllers or long-term nonprogressor models. However, there is a less-known group of individuals, termed viremic nonprogressors (VNPs), who maintain stable CD4+ T cell counts despite high plasma viremia. The mechanisms involved in this remarkable control of HIV-1 pathogenesis clearly have implications for the development of new drugs and vaccines. We show here for the first time that VNPs have immune responses and HIV-gag evolution similar to those of standard progressors. Remarkably, we demonstrate that the mechanism of pathogenesis control in these individuals differs from some elite controllers that are reported to have improved immune control. This is noteworthy since it opens the door to new, as-yet-unknown mechanisms for HIV control. Our novel results advance the understanding of mechanisms involved in viremic nonprogression and suggest that there are alternative mechanisms to the adaptive immune responses for an effective control of viral pathogenesis.

Keywords: CTL response; HIV-1; progression; viral pathogenesis; viremic nonprogressors.

PubMed Disclaimer

Figures

FIG 1
FIG 1
Epitope-specific CTL response in VNPs and SPs. (a and b) Map of the specific overlapping epitopes that generated IFN-γ responses for VNPs and SPs, respectively. Data are presented as spot-forming cells (SFC) per 106 PBMCs. Specifically, for VNPs we were able to compare samples from t0 (light orange) with those from t3 (dark orange). (c) Specific CTL response magnitude. The magnitude of the response was the additive response of all the positive wells measured as SFC/106 PBMCs. VNP data are represented in light orange (t0) or dark orange (t3). SP data are presented in dark blue (t3). (d) Specific CTL response breadth.
FIG 2
FIG 2
Phylogenetic tree of gag clonal sequences from VNPs and SPs. VNP sequences are indicated in orange, and SP sequences are indicated in blue. Sequences from t0 are represented as open symbols and from t3 as filled symbols.
FIG 3
FIG 3
Evolution analysis of the gag sequences. Diversity is measured as the p-distance measuring the proportion of changes in each sequence calculated as nucleotide (synonymous) or amino acid changes (nonsynonymous). (a and b) Intragroup distances. Variability in each subject's group of sequences was determined at each time point. Each participant is represented by a different shade of orange (VNPs) or blue (SPs). (c) Intergroup distances. Evolution over time was determined for each participant. VNP samples are indicated by orange symbols and SP samples by blue. Synonymous evolution is indicated by circles and nonsynonymous evolution by squares. (d) Intergroup distance ratio. pNS/pS ratios were determined. VNP samples are indicated in orange and SP samples in blue.
FIG 4
FIG 4
Genetic variation in epitopes with positive responses in each subject. Blue boxes represents the relative intensity IFN-γ responses in each epitope. VNP-4 responses are not shown since they are outside the sequenced area. The SP-9 immune response was not determined due to the bad cell quality. Open boxes represents HLA-associated epitopes.

Similar articles

Cited by

References

    1. Mellors JW, Muñoz A, Giorgi JV, Margolick JB, Tassoni CJ, Gupta P, Kingsley LA, Todd JA, Saah AJ, Detels R, Phair JP, Rinaldo CR. 1997. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med 126:946–954. doi:10.7326/0003-4819-126-12-199706150-00003. - DOI - PubMed
    1. Rodríguez B, Sethi AK, Cheruvu VK, Mackay W, Bosch RJ, Kitahata M, Boswell SL, Mathews WC, Bangsberg DR, Martin J, Whalen CC, Sieg S, Yadavalli S, Deeks SG, Lederman MM. 2006. Predictive value of plasma HIV RNA level on rate of CD4 T-cell decline in untreated HIV infection. JAMA 296:1498–1506. doi:10.1001/jama.296.12.1498. - DOI - PubMed
    1. Choudhary SK, Vrisekoop N, Jansen CA, Otto SA, Schuitemaker H, Miedema F, Camerini D. 2007. Low immune activation despite high levels of pathogenic human immunodeficiency virus type 1 results in long-term asymptomatic disease. J Virol 81:8838–8842. doi:10.1128/JVI.02663-06. - DOI - PMC - PubMed
    1. Silvestri G. 2008. AIDS pathogenesis: a tale of two monkeys. J Med Primatol 37(Suppl 2):S6–S12. doi:10.1111/j.1600-0684.2008.00328.x. - DOI - PubMed
    1. Shaw JM, Hunt PW, Critchfield JW, McConnell DH, Garcia JC, Pollard RB, Somsouk M, Deeks SG, Shacklett BL. 2013. Short communication: HIV+ viremic slow progressors maintain low regulatory T cell numbers in rectal mucosa but exhibit high T cell activation. AIDS Res Hum Retroviruses 29:172–177. doi:10.1089/aid.2012.0268. - DOI - PMC - PubMed

Publication types

MeSH terms

Substances