Evolution of human immunodeficiency virus type 2 coreceptor usage, autologous neutralization, envelope sequence and glycosylation

Abstract

To investigate why human immunodeficiency virus type 2 (HIV-2) is less virulent than HIV-1, the evolution of coreceptor usage, autologous neutralization, envelope sequence and glycosylation was studied in sequentially obtained virus isolates and sera from four HIV-2-infected individuals. Neutralization of primary HIV-2 isolates was tested by a cell line-based assay and IgG purified from patients' sera. Significant autologous neutralization was observed for the majority (39 of 54) of the HIV-2 serum–virus combinations tested, indicating that neutralization escape is rare in HIV-2 infection. Furthermore, sera from 18 HIV-2 patients displayed extensive heterologous cross-neutralization when tested against a panel of six primary HIV-2 isolates. This indicates that HIV-2 is intrinsically more sensitive to antibody neutralization than HIV-1. In line with earlier reports, HIV-2 isolates could use several alternative receptors in addition to the major coreceptors CCR5 and CXCR4. Intrapatient evolution from CCR5 use to CXCR4 use was documented for the first time. Furthermore, CXCR4 use was linked to the immunological status of the patients. Thus, all CXCR4-using isolates, except one, were obtained from patients with CD4 counts below 200 cells μl−1. Sequence analysis revealed an association between coreceptor usage and charge of the V3 loop of the HIV-2 envelope, as well as an association between the rate of disease progression and the glycosylation pattern of the envelope protein. Furthermore, HIV-2 isolates had fewer glycosylation sites in the V3 domain than HIV-1 (two to three versus four to five). It is proposed here that HIV-2 has a more open and accessible V3 domain than HIV-1, due to differences in glycan packing, and that this may explain its broader coreceptor usage and greater sensitivity to neutralizing antibodies.

Baseline Susceptibility of Primary HIV-2 to Entry Inhibitors

“…Clinical trials are therefore needed to determine if the MVC dosages recommended in HIV-1 infection are also effective for HIV-2 infection. This may prevent the administration of subtherapeutic dosages that favour the selection of X4 variants which, in HIV-2, have been associated not only with CD4 depletion and disease progression [2], but also with resistance to neutralization [16]. Similarly to previous results obtained with RANTES for HIV-2 [17] and with TAK-779 and C-C chemokines for HIV-1 [8,9], MVC inhibits the replication of R5 HIV-2 variants isolated from AIDS patients with significantly higher IC 50s than R5 variants isolated from asymptomatic patients, this being inversely associated with the number of CD4 + T-cells.…”

“…In contrast to HIV-1, HIV-2 may enter cells without binding to CD4, and by using multiple alternative coreceptors besides CCR5 and CXCR4 [2,3]. This suggests that maraviroc (MVC), a CCR5 antagonist, might also have limited activity against HIV-2.…”

Synonymous Substitution Rates Predict HIV Disease Progression as a Result of Underlying Replication Dynamics

“…P3P4, P7P8, and P9P10 are HIV-2 transmission chains (see Methods); the estimates therefore represent the mean evolutionary rate in two infected patients. The estimates for Shi et al [68] represent mean substitution rates in four individuals for which only limited sequences were available (see Methods). Found at doi:10.1371/journal.pcbi.0030029.st004 (60 KB DOC).…”

HIV-2 A-subtype gp125C2-V3-C3 mutations and their association with CCR5 and CXCR4 tropism

“…2; Table S1). In an interesting study, Shi and colleagues have observed in a four-PBMC-passage stock the conservation of L319R V3 , I320R V3 and K338E C3 mutations in viral isolates that efficiently use CXCR4 [54]. Probably, V3 and C3 interaction at these positions, which flank the amino acids F337 C3 and F321 V3 , which are already involved in the predicted non-covalent interaction [41].…”

“…In HIV-2, the net charge of the V3-loop is a determinant of co-receptor selection, like in HIV-1 [51][52][53][54].…”