Escape of HIV-1 is associated with lack of V3 domain-specific antibodies in vivo

Abstract

SUMMARYThis study was performed to analyse correlates of viral escape in AIDS patients. Peripheral blood mononuclear cells (PBMC) from HIV ¹ donors were inoculated with AIDS patients' serum to detect neutralization-resistant cell-free virus. Infectious virus was detected by polymerase chain reaction (PCR) and analysed by sequencing the V3 region. The escaped virus species was compared with all V3 virus variants found in the patients' PBMC and plasma. In one patient escaped virus was also compared with variants found in CD4 þ T cells isolated by FACS from blood, spleen and lymph node. The frequency of the virus variants was determined by cloning and sequence analysis of 20 V3 clones for each PCR amplification. To monitor anti-V3 antibodies by ELISA, each V3 sequence was expressed as fusion with glutathione S-transferase (GST-V3). In our AIDS patients, a V3-directed antibody response against the infectious virus V3 loop was not detectable. In contrast, virus variants unable to infect the donor PBMC in vitro were well recognized by homologous V3-directed antibody. After an interval of 1 year the frequency of these variants clearly decreased, while at the same time the escaped variants grew out and finally represented the predominant viral species both in plasma and PBMC. The infectious variants lacking V3 antibody response were also predominant in CD4 þ T cells in spleen and lymph node. Our data indicate that the escape of virus variants is closely related to the lack of V3-directed antibody.

Immune Responses to HIV Gp120 that Facilitate Viral Escape

“…This has particularly been described for the V3 loop [39,53,89]. While some authors describe a lack of V3-specific neutralizing antibodies in patients who develop AIDS [89], others have found that neutralizing antibodies for one strain of HIV-1 to the V3 loop could fail to neutralize another strain of the same virus and even enhance infection in a third strain [53]. These findings have identified the variable position 311 proximal to the conserved GPGR motif at the top of the V3 crown as important for viral sensitivity to neutralization or enhancement by antibodies.…”

“…It is thought that these loops change in structure and conformation from time to time, thereby allowing the virus to elude the immune response. This has particularly been described for the V3 loop [39,53,89]. While some authors describe a lack of V3-specific neutralizing antibodies in patients who develop AIDS [89], others have found that neutralizing antibodies for one strain of HIV-1 to the V3 loop could fail to neutralize another strain of the same virus and even enhance infection in a third strain [53].…”

Molecular Evolution of Human Immunodeficiency Virus env in Humans and Monkeys: Similar Patterns Occur during Natural Disease Progression or Rapid Virus Passage

“…3). Many mutations were located in V3, a region that contains linear and discontinuous antigenic determinants (9,18,39) that can change during disease development and immune escape (37,38,41). Some amino acid substitutions led to three new and loss of two potential N-linked glycosylation sites, which in turn might result in changes in conformation and immune recognition of gp120 (3,12,14,29,30,35,47,50).…”

Antibodies That Are Cross-Reactive for Human Immunodeficiency Virus Type 1 Clade A and Clade B V3 Domains Are Common in Patient Sera from Cameroon, but Their Neutralization Activity Is Usually Restricted by Epitope Masking

“…Serum adsorption studies have shown that type-specific V3-directed antibodies contribute to the neutralization of autologous virus and control of in vivo infection for some patients (6,41,42). The existence of V3 epitopes that mediate the neutralization of primary virus isolates and are conserved within clade B was shown by the demonstration that polyclonal V3-reactive antibodies isolated from North American patient sera possessed potent neutralizing activity against a number of clade B primary isolates (26).…”