Human Immunodeficiency Virus Type 1 Glycoprotein 120-Specific T Lymphocytes Provide Intermolecular Help for Anti-CD4 Autoantibody Production in Exposed Uninfected Subjects

Abstract

Anti-CD4 antibodies have been documented in about 10-20% of HIV-infected patients. This autoimmune response could be triggered by increased CD4 processing and unveiling of hidden (cryptic) epitopes. Multiple markers of exposure to HIV have been described in exposed uninfected individuals. Here, we investigated the mechanisms underlying the generation of anti-CD4 antibodies in a cohort of 54 seronegative exposed uninfected individuals. We identified anti-CD4 antibodies above normal levels in 16 of 47 (34%) exposed uninfected subjects. The fine specificity of these antibodies was different in this cohort when compared with those found in HIV+ patients. This suggested the possibility of different mechanisms underlying the generation of anti-CD4 antibodies in these two groups. Indeed, in exposed uninfected subjects, we found circulating CD4 T cells specific for gp120, but not for CD4. In contrast, HIV-1-seropositive patients had peripheral blood T cells specific for both molecules. Noncovalent binding of gp120 to soluble CD4 enhanced activation of gp120-specific T lymphocytes in exposed uninfected subjects, but not in HIV+ subjects. Moreover, gp120-specific T cells isolated from exposed uninfected, but not from HIV+, subjects provided help for anti-CD4 antibody production by B cells pulsed with CD4-gp120 complex. We conclude that gp120-specific T cells are present in exposed uninfected individuals, and can provide intermolecular help for anti-CD4 antibody production. This mechanism is distinct from that found in HIV-1-seropositive patients and may play a protective role against HIV-1 infection in vivo.

Small Ruminant Lentiviruses and Human Immunodeficiency Virus: Cousins that Take a Long View

“…This appears to be the case in some individuals infected with HIV who exhibit transient infection. Virus elimination in these individuals correlates with the presence of both CD4+ and CD8+ T cell responses and neutralizing antibodies with specificity particularly for gp41 [350][351][352]. The mechanism underlying SRLV clearance by lambs in the study by Herrmann-Hoesing and colleagues [178] is unknown.…”

Dissociation of CD4+ cell counts from viral load and association with immune complexes in HIV+ hemophilia patients

“…Several recent reports described individual differences in resistance to infection, progression of disease, as well as response to antiretroviral treatment [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]. These differences might be attributable to (a) infection with slowly replicating virus mutants [22,23]; (b) genetically determined non-expression of HIV receptors on host cells [24,25], or individual differences of the host immune response concerning; (c) the cytotoxic and/or non-cytotoxic response of CD8 + lymphocytes to the retrovirus [26][27][28][29]; or (d) HIV-induced autoimmune mechanisms such as formation of antibodies and immune complexes against circulating CD4 + blood lymphocytes [8][9][10][11]15,[30][31][32][33][34][35][36][37][38][39][40].…”

Is Autoimmunity a Component of Natural Immunity to HIV?

“…Strikingly, neutralizing responses were statistically related to the presence of anti-cell antibodies to surface antigens exposed on lymphocytes, possibly involved in the process of virus infection, such as HLA class I, CD4 and CCR5. Anti-HLA and anti-CD4 antibodies, found in exposed subjects, were shown to recognize conformational epitopes, induced by the interaction with gp120, and to display HIV-neutralizing properties [9,10,21,51]. Anti-CCR5 IgG and IgA antibodies, found in a subset of exposed individuals, shared the same specificity to the first external loop of the receptor and inhibited specifically R5-mediated HIV infectivity [93,6,91].…”

“…Anti-CD4 antibodies are triggered by the unmasking of cryptic/conformational epitopes, that become exposed after gp120-CD4 binding [51]. Anti-HLA responses depend on molecular mimicry between HIV glycoproteins and HLA domains [37].…”