Cryptic nature of envelope V3 region epitopes protects primary monocytotropic human immunodeficiency virus type 1 from antibody neutralization

Abstract

Characterization of biological and immunological properties of human immunodeficiency virus type 1 (HIV-1) is critical to developing effective therapies and vaccines for AIDS. With the use of a novel CD4+ T-cell line (PM-1) permissive to infection by both monocytotropic (MT) and T-cell-tropic virus types, we present a comparative analysis of the immunological properties of a prototypic primary MT isolate of HIV-1 strain JR-CSF (MT-CSF) with those of a T-cell-tropic variant (T-CSF) of the same virus, which emerged spontaneously in vitro. The parental MT-CSF infected only PM-1 cells and was markedly resistant to neutralization by sera from HIV-1-infected individuals, rabbit antiserum to recombinant MT-CSF gpl20, and anti-V3 monoclonal antibodies. The T-CSF variant infected a variety of CD4+ T-cell lines, contained positively charged amino acid substitutions in the gpl20 V3 region, and was highly sensitive to antibody neutralization. Neutralization and antibody staining of T-CSF-expressing cells were significantly inhibited by HIV-1 V3 peptides; in contrast, the MT strain showed only weak V3-specific binding of polyclonal and monoclonal antibodies. Exposure of PM-1 cells to a mixture of both viruses in the presence of human anti-HIV-1 neutralizing antiserum resulted in infection with only MT-CSF. These results demonstrate that although the V3 region of MT viruses is immunogenic, the target epitopes in the V3 principal neutralizing domain on the membrane form of the MT envelope appear to be cryptic or hidden from blocking antibodies.

Human immunodeficiency virus type 1 neutralization is determined by epitope exposure on the gp120 oligomer.

“…However, one recent study (61) presented evidence that immunization of mice with soluble, gp41-associated oligomeric gp120 resulted in a low frequency of V3 loop reactivity, suggesting that the V3 loop may not be an immunodominant domain in oligomeric gp120. This conclusion is in accord with the fmding that the V3 loop of a monocytotropic HIV-1 primary isolate appears to be cryptic on the virion surface (62). Such masking of V3 epitopes on non-cell line-passaged virus may explain our recent observation that HIVol primary isolates are relatively poorly neutralized by V3 mAbs, which are potent neutralizers of T cell line-adapted viruses such as the Hxl0 clone used in the present study (63,64).…”

Antagonistes du récepteur CCR5 et infection par le VIH-1 : bases et conséquences de cette approche thérapeutique

“…De nombreux facteurs peuvent participer à la prédominance des souches R5 pendant la plus grande partie de la phase chronique de l'infection à VIH-1. Certains auteurs soutiennent l'idée que la réponse immunitaire humorale [18] ou cytotoxique [19] est plus efficace contre les souches X4, ainsi le système immunitaire devrait-il être affaibli par les souches R5 afin de permettre l'expansion des souches X4. D'autres pensent que cette prédominance est due à une plus grande capacité réplicative des souches R5.…”

Identifying epitopes of HIV-1 that induce protective antibodies

“…Similarly, the conclusion that V3-specific antibodies are ineffective for neutralizing primary isolates was based on inefficient depletion of antibodies from HIV-1 + sera with linear V3 peptides -a process that would have failed to effectively remove antibodies that are specific for conformation-sensitive V3 epitopes 97,98 . Moreover, careful review of early studies, as well as more recent data published by several groups, shows that epitopes in the V3 loop are not cryptic but are at least partially displayed on the surface of R5 virus particles and R5virus-infected cells 36,37,89,90,99,100 , and that V3-specific monoclonal antibodies can neutralize R5 as well as X4 viruses 86,87,89,90,101 .…”