Resistance to Replication of Human Immunodeficiency Virus Challenge in SCID-Hu Mice Engrafted with Peripheral Blood Mononuclear Cells of Nonprogressors Is Mediated by CD8⁺T Cells and Associated with a Proliferative Response to p24 Antigen

Abstract

High levels of resistance to challenge with human immunodeficiency virus type 1 SF162 were observed in animals engrafted with peripheral blood mononuclear cells of four long-term nonprogressors (LTNPs). Resistance was abrogated by depletion of CD8 ؉ T cells in vivo and was observed only in LTNPs with proliferative responses to p24. In a subgroup of nonprogressors, CD8؉ T cells mediated restriction of challenge viruses, and this response was associated with strong proliferative responses to p24 antigen. Although patients with normal CD4ϩ T-cell counts and low levels of virus in plasma are a heterogeneous group, a small subgroup of patients with truly nonprogressive human immunodeficiency virus (HIV) infection likely hold important clues to the basis of an effective immune response to HIV. It now appears clear that a large fraction of patients previously considered long-term nonprogressors (LTNPs) ultimately show a decline of CD4 ϩ -T-cell numbers. Members of a small subpopulation (Ͻ0.8% of HIV-infected individuals) show no signs of progression over a 10-year period (12,22,23,36). Extensive studies have demonstrated strong cellular and humoral HIVdirected responses in LTNPs (2,6,7,15,18,29,31,32). Regardless of the host or virus factors involved in nonprogression in these patients, a clear demonstration of immunity-mediated resistance to challenge virus and targets of such a response within HIV would enhance development of an effective HIV vaccine. Recently we established a human HIV-peripheral blood mononuclear cell (PBMC)-SCID mouse model, a modification of the method developed by Mosier et al. (13,26,28), to study the PBMC of infected patients (5). We determined whether PBMC of LTNPs support replication of patients' autologous viruses in this model and further whether these PBMC mediate restriction of challenge-virus replication.Engraftment of CB-17 SCID mice and sample collection were performed as previously described (5). Animals were challenged intraperitoneally with HIV SF162 on day 7 and sacrificed on day 21. To deplete CD8 ϩ T cells, on day 6 animals received 0.2 mg of 7ptF9 anti-CD8 monoclonal or 833ICG isotype control antibody (Coulter, Hialeah, Fla.). In preliminary experiments the 7ptF9 antibody was not blocked by the detecting antibody to CD8. Because there is no substantial lymphopoiesis, 7ptF9 treatment resulted in high-level (Ͼ98%) depletion of CD8 ϩ T cells throughout the experimental period. Proviral DNA and plasma viral RNA assays were performed using the Perkin-Elmer (Foster City, Calif.) model 7700 sequence detector. Dunnett's test for multiple comparisons was used to compare the percentages of CD4 ϩ T cells and the Wilcoxon two-sample test was used with the Bonferroni multiple-testing correction to compare levels of virus in plasma and provirus in spleen between groups of animals. In vitro cultures were performed as previously described (3). Standard enzyme-linked immunosorbent assays were used to quantify the CC chemokines MIP-1␣, MIP-1␤, and RANTES (R&D Systems, Minneapolis, Minn.) or p24 ...

Depletion of circulating natural type 1 interferon-producing cells in HIV-infected AIDS patients

“…35,36 Several factors, both host and virus related, have been implicated in the resistance to disease progression. These include CCR5 37 and CCR5 promoter 38 genotypes, heterozygosity (HLA class I loci), 39 the presence of the HLA B*5701 allele, 40 and CD8 ϩ cytotoxic 41,42 and noncytotoxic cellular immune responses [43][44][45] Besides the known antiviral and adjuvant effects of type I IFN, 17,21,23,24,26,46 these cytokines inhibit HIV infection. [18][19][20]47 In this study, we show that (1) the circulating IPC number and their function are increased in LTSs and (2) LTSs with a high IPC number have significantly lower viral loads than those with a low IPC number (Figures 2,4).…”

HIV controllers: how do they tame the virus?

“…The quantification of HIV in plasma revealed: (i) that patients enrolled in LTNP cohorts who remained asymptomatic and who maintained high CD4 + T-cell counts were usually those in whom viral load was lowest [6]; and (ii) that, interestingly, some HIV-1-infected individuals consistently maintained undetectable plasma viral loads [2,10,11]. We chose to call these individuals with an undetectable plasma viral load ''HIV controllers'' (HICs) [11], although they are also known as ''elite controllers,'' ''elite suppressors'' [12], or ''elite nonprogressors'' [13].…”

Isolation and Characterization of Replication-Competent Human Immunodeficiency Virus Type 1 from a Subset of Elite Suppressors

“…CD8 ϩ T cells from LTNP are very efficient at controlling viral replication in vitro (6,11) and in vivo (16). More recent studies of cytotoxic-T-lymphocyte (CTL) responses in LTNP have shown that, whereas there is no correlation between the frequency of gamma interferonsecreting CD8…”