Increased Neutralization Sensitivity and Reduced Replicative Capacity of Human Immunodeficiency Virus Type 1 after Short-Term In Vivo or In Vitro Passage through Chimpanzees

Abstract

Development of disease is extremely rare in chimpanzees when inoculated with either T-cell-line-adapted neutralization-sensitive or primary human immunodeficiency virus type 1 (HIV-1), at first excluding a role for HIV-1 neutralization sensitivity in the clinical course of infection. Interestingly, we observed that short-term in vivo and in vitro passage of primary HIV-1 isolates through chimpanzee peripheral blood mononuclear cells (PBMC) resulted in a neutralization-sensitive phenotype. Furthermore, an HIV-1 variant reisolated from a chimpanzee 10 years after experimental infection was still sensitive to neutralization by soluble CD4, the CD4 binding site recognizing antibody IgG1b12 and autologous chimpanzee serum samples, but had become relatively resistant to neutralization by polyclonal human sera and neutralizing monoclonal antibodies. The initial adaptation of HIV-1 to replicate in chimpanzee PBMC seemed to coincide with a selection for viruses with low replicative kinetics. Neither coreceptor usage nor the expression level of CD4, CCR5, or CXCR4 on chimpanzee PBMC compared to human cells could explain the phenotypic changes observed in these chimpanzee-passaged viruses. Our data suggest that the increased neutralization sensitivity of HIV-1 after replication in chimpanzee cells may in part contribute to the long-term asymptomatic HIV-1 infection in experimentally infected chimpanzees.

Reversal of Human Immunodeficiency Virus Type 1 IIIB to a Neutralization-Resistant Phenotype in an Accidentally Infected Laboratory Worker with a Progressive Clinical Course

“…Based on this observation, we conclude that the neutralization resistance of HIV may be considered an escape mechanism from humoral immunity. The clinical relevance of HIV-1 neutralization resistance is in line with our finding that a IIIB variant reisolated from an experimentally infected chimpanzee after 10 years of asymptomatic HIV infection was still sensitive to neutralization by CD4-binding-site-directed antibodies and sCD4 (5). Symptom-free follow-up of this animal has now extended to more than 18 years.…”

Virus Isolates during Acute and Chronic Human Immunodeficiency Virus Type 1 Infection Show Distinct Patterns of Sensitivity to Entry Inhibitors

“…Primary HIV-1 isolates have proven to be relatively resistant to soluble CD4, probably due to the fact that these viruses have adapted to replicate in the presence of neutralizing antibodies to CD4BS, which are highly prevalent in patient sera (3,12,23,37,57,58,60,63,65,86). HIV-1 cultured in the absence of neutralizing antibodies in vitro rapidly adapts, and more-neutralization-sensitive variants emerge (6,56,57,70,100). This change in phenotype has been attributed to an alternate interaction with CD4, potentially generating a greater affinity of the envelope for CD4 while simultaneously exposing neutralization epitopes, particularly those associated with the CD4 binding site (70).…”

“…The period that the virus replicated in absence of CD4BS antibodies during acute infection in our cohort was less than 3 months, which may be too short to allow reversion of the CD4BS-resistant phenotype (which the virus probably obtained in the previous host) to a CD4BS-sensitive stage. In comparison, emergence of CD4-sensitive quasispecies in vitro has been reported after 19 weeks of continuous culture (70) but may also occur more rapidly, depending on the virus isolate and/or target cells (6,7,104). It is also possible that in vivo even in the absence of neutralizing antibodies to CD4BS or additional sites, other selection pressures exist that prevent the conversion of gp120 to the neutralization-sensitive phenotype.…”

“…How the viral envelope engages CD4 and which epitopes are exposed upon CD4 binding shapes the subsequent interaction with the coreceptor but also influences the sensitivity to neutralization. In the absence of neutralizing antibodies in vitro, the virus readily adapts to optimize usage of the receptor (6,56,57,70,100). In vivo, selective pressure of antibodies directed to the CD4BS is thought to prevent this conformation of gp120.…”

Effective activation alleviates the replication block of CCR5-tropic HIV-1 in chimpanzee CD4+ lymphocytes

“…In an initial set of experiments, we thus used phytohaemaglutinin (PHA) to activate chimpanzee CD4+ T lymphocytes as previously described (Beaumont et al, 2000; Gendelman et al, 1991; Nguyen et al, 2006; Schuitemaker et al, 1993; Shibata et al, 1995; Watanabe et al, 1991). Replication of the X4-tropic HIV-1 SG3 strain in these PHA-activated T cell cultures was highly variable among chimpanzee donors (n=8, day 8 post infection median p24 = 13ng/ml, range 0-72 ng/ml), ranging from no replication (n=2) to levels 10-fold lower compared to human donors (n=6, day 8 post-infection median p24 = 193 ng/ml, range 120-430 ng/ml) (Figure 1A).…”