Study of the V3 Loop as a Target Epitope for Antibodies Involved in the Neutralization of Primary Isolates versus T-Cell-Line-Adapted Strains of Human Immunodeficiency Virus Type 1

Abstract

Previous studies characterized the third variable (V3) loop of the envelope gp120 as the principal neutralizing determinant for laboratory T-cell-line-adapted (TCLA) strains of human immunodeficiency virus type 1 (HIV-1). However, primary viruses isolated from infected individuals are more refractory to neutralization than TCLA strains, suggesting that qualitatively different neutralizing antibodies may be involved. In this study, we investigated whether the V3 loop constitutes a linear target epitope for antibodies neutralizing primary isolates. By using peptides representative of the V3 regions of various primary isolates, an early, relatively specific and persistent antibody response was detected in sera from HIV-infected patients. To assess the relationship between these antibodies and neutralization, the same peptides were used in competition and depletion experiments. Addition of homologous V3 peptides led to a competitive inhibition in the neutralization of the TCLA strain HIVMN/MT-4 but had no effect on the neutralization of the autologous primary isolate. Similarly, the removal of antibodies that bind to linear V3 epitopes resulted in a loss of HIVMN/MT-4 neutralization, whereas no decrease in the autologous neutralization was measured. The different roles of V3-specific antibodies according to the virus considered were thereby brought to light. This confirmed the involvement of V3 antibodies in the neutralization of a TCLA strain but emphasized a more pronounced contribution of either conformational epitopes or epitopes outside the V3 loop as targets for antibodies neutralizing primary HIV-1 isolates. This result underlines the need to focus on new vaccinal immunogens with epitopes able to induce broadly reactive and efficient antibodies that neutralize a wide range of primary HIV-1 isolates.

Short Communication:Neutralizing Antibody Responses in Recent Seroconverters with HIV-1 Subtype C Infections in India

“…The high degree of conservation in the V3 region supports the data suggesting that this region may not be the target of the potent neutralizing responses in these individuals and perhaps anti-V3 antibodies in subtype C infection may not be of great biological relevance in driving the viral escape from the neutralization response. The neutralization response obtained in our study was not associated with any particular mutation in the V3 region, which may be an indication that other variable regions of the HIV-1 envelope might be involved in generating a neutralization response, 27,35 which needs to be studied in greater detail. However, an antibody response could be generated by the interaction of the V3 loop with other regions of gp120, which may play a role in neutralization.…”

Identifying epitopes of HIV-1 that induce protective antibodies

“…For example, we now know that whereas isolate-specific V3-specific antibodies are produced early after infection or immunization 68,69,82 , broadly reactive V3-specific antibodies are characteristic of a more mature immune response 86,88 . 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 .…”

Coinoculation with hepatitis B surface and core antigen promotes a Th1 immune response to a multiepitopic protein of HIV‐1

“…Second, the protein also includes B-cell epitopes associated with several immuneeffector mechanisms. [46][47][48][49][50][51][52][53] Our results show that CR3 is able to induce an IgG recognition pattern in sera to HIV-1 proteins, after i.n. and s.c. immunization, similar to seropositive persons.…”