Human Immunodeficiency Virus Type 1 Variants Isolated from Single Plasma Samples Display a Wide Spectrum of Neutralization Sensitivity

CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) variants evolve from CCR5-using (R5) variants relatively late in the natural course of infection in 50% of HIV-1 subtype B-infected individuals and subsequently coexist with R5 HIV-1 variants. This relatively late appearance of X4 HIV-1 variants is poorly understood. Here we tested the neutralization sensitivity for soluble CD4 (sCD4) and the broadly neutralizing antibodies IgG1b12, 2F5, 4E10, and 2G12 of multiple coexisting clonal R5 and (R5)X4 (combined term for monotropic X4 and dualtropic R5X4 viruses) HIV-1 variants that were obtained at two time points after the first appearance of X4 variants in five participants of the Amsterdam Cohort Studies on HIV-1 infection and AIDS. Recently emerged (R5)X4 viruses were significantly more sensitive to neutralization by the CD4-bindingsite-directed agents sCD4 and IgG1b12 than their coexisting R5 viruses. This difference was less pronounced at the later time point. Early (R5)X4 variants from two out of four patients were also highly sensitive to neutralization by autologous serum (50% inhibition at serum dilutions of >200). Late (R5)X4 viruses from these two patients were neutralized at lower serum dilutions, which suggested escape of X4 variants from humoral immunity. Autologous neutralization of coexisting R5 and (R5)X4 variants was not observed in the other patients. In conclusion, the increased neutralization sensitivity of HIV-1 variants during the transition from CCR5 usage to CXCR4 usage may imply an inhibitory role for humoral immunity in HIV-1 phenotype evolution in some patients, thus potentially contributing to the late emergence of X4 variants.Entry of human immunodeficiency virus type 1 (HIV-1) into a host cell is mediated by binding of the viral envelope glycoprotein 120 (gp120) to CD4 and a coreceptor, of which CCR5 and CXCR4 are the most important on primary cells (7,8,9). Primary HIV-1 infections are generally established by R5 viruses, which remain present throughout the course of infection (27). In approximately 50% of therapy-naive individuals infected with subtype B HIV-1, X4 viruses evolve from R5 variants, preceding an increased CD4 ϩ T-cell decline and accelerated progression to AIDS (4,24,27,30).The relatively late appearance of X4 HIV-1 variants is poorly understood. R5 and X4 subtype B HIV-1 variants can genetically be distinguished by the absence or presence of a positively charged amino acid on positions 11 and/or 25 in the third variable loop (V3) of the gp120 envelope (10). In vitro experiments revealed that these mutations in V3 (6), as well as other single or double mutations in V3 and other domains of gp120 (2, 12), are sufficient to change coreceptor usage. However, in spite of the high mutation rate of HIV-1, X4 viruses do not evolve rapidly in vivo and not in all infected patients. Moreover, the earliest detectable X4 variants in vivo show more than only one or two amino acid substitutions compared to coexisting R5 variants (16), suggestive of compensatory mutations. The...

Section: Discussionmentioning

confidence: 57%

Increased Neutralization Sensitivity of Recently Emerged CXCR4-Using Human Immunodeficiency Virus Type 1 Strains Compared to Coexisting CCR5-Using Variants from the Same Patient

Bunnik

Quakkelaar

Nuenen

et al. 2007

“…Alternatively, the contemporaneous presence of both neutralization escape and sensitive variants may suggest the emergence of escape variants before the clearance of sensitive strains. Indeed, this dynamic has previously been observed during chronic HIV-1 infection (35,42,47). The presence of variants that were sensitive to neutralization was not surprising given that we selected cases in which there was evidence for neutralization of the maternal primary isolate by her autologous plasma.…”

Section: Discussionmentioning

confidence: 99%

Neutralization Escape Variants of Human Immunodeficiency Virus Type 1 Are Transmitted from Mother to Infant

Wu¹,

Parast²,

Richardson

et al. 2006

276

258

Maternal passive immunity typically plays a critical role in protecting infants from new infections; however, the specific contribution of neutralizing antibodies in limiting mother-to-child transmission of human immunodeficiency virus type 1 is unclear. By examining cloned envelope variants from 12 transmission pairs, we found that vertically transmitted variants were more resistant to neutralization by maternal plasma than were maternal viral variants near the time of transmission. The vertically transmitted envelope variants were poorly neutralized by monoclonal antibodies biz, 2G12, 2F5, and 4E10 individually or in combination. Despite the fact that the infant viruses were among the most neutralization resistant in the mother, they had relatively few glycosylation sites. Moreover, the transmitted variants elicited de novo neutralizing antibodies in the infants, indicating that they were not inherently difficult to neutralize. The neutralization resistance of vertically transmitted viruses is in contrast to the relative neutralization sensitivity of viruses sexually transmitted within discordant couples, suggesting that the antigenic properties of viruses that are favored for transmission may differ depending upon mode of transmission.

“…Although these NAb ultimately reach fairly high titers, escape mutants are selected rapidly due to their high levels of ongoing viral replication (50,59). Other studies have shown that chronically HIV-1-infected patients also develop NAb against earlier viral isolates but show little neutralization of contemporaneous virus (53,55).…”

mentioning

confidence: 99%

Neutralizing Antibodies Do Not Mediate Suppression of Human Immunodeficiency Virus Type 1 in Elite Suppressors or Selection of Plasma Virus Variants in Patients on Highly Active Antiretroviral Therapy

Bailey

Lassen

Yang

et al. 2006

158

147

Neutralizing antibodies (NAb) against autologous virus can reach high titers in human immunodeficiency virus type 1 (HIV-1)-infected patients with progressive disease. Less is known about the role of NAb in HIV-1-infected patients with viral loads of <50 copies/ml of plasma, including patients on effective highly active antiretroviral therapy (HAART) and elite suppressors, who control HIV-1 replication without antiretroviral therapy. In this study, we analyzed full-length env sequences from plasma viruses and proviruses in resting CD4؉ T cells of HAART-treated patients, elite suppressors, and untreated HIV-1-infected patients with progressive disease. For each patient group, we assessed plasma virus neutralization by autologous, contemporaneous plasma. The degree of env diversity, the number of N-linked glycosylation sites, and the lengths of variable loops were all lower in elite suppressors than in HAART-treated and untreated viremic patients. Both elite suppressors and HAART-treated patients had lower titers of NAb against HIV-1 lab strains than those of untreated viremic patients. Surprisingly, titers of NAb against autologous, contemporaneous plasma viruses were similarly low in chronic progressors, elite suppressors, and HAART-treated patients. In elite suppressors and HAART-treated patients, titers of NAb against autologous plasma viruses also did not differ significantly from titers against autologous proviruses from resting CD4 ؉ T cells. These results suggest that high-titer NAb are not required for maintenance of viral suppression in elite suppressors and that NAb do not select plasma virus variants in most HAART-treated patients. Both drug-mediated and natural suppression of HIV-1 replication to levels below 50 copies/ml may limit the stimulation and maintenance of effective NAb responses.