Late seroconversion in HIV-resistant Nairobi prostitutes despite pre-existing HIV-specific CD8+ responses

Abstract

Resistance to HIV infection in a small group of Kenyan sex workers is associated with CD8+-lymphocyte responses to HIV cytotoxic T-lymphocyte (CTL) epitopes. Eleven prostitutes meeting criteria for HIV resistance seroconverted between 1996 and 1999. The occurrence and specificity of preexisting HIV-1 epitope-specific responses were examined using the IFN-gamma enzyme-linked immunospot assay, and any epitopes recognized were cloned and sequenced from the infecting viral isolate. Immunologic and behavioral variables were compared between late seroconverters and persistently uninfected sex worker controls. HIV-1 CTL epitope responses were present in four of six cases, 5-18 months before seroconversion, and their presence was confirmed by bulk CTL culture. A possible viral escape mutation was found in one of six epitopes. The key epidemiologic correlate of late seroconversion was a reduction in sex work over the preceding year. In persistently uninfected controls, a break from sex work was associated with a loss of HIV-specific CD8+ responses. Late seroconversion may occur in HIV-1-resistant sex workers despite preceding HIV-specific CD8+ responses. Seroconversion generally occurs in the absence of detectable CTL escape mutations and may relate to the waning of HIV-specific CD8+ responses due to reduced antigenic exposure.

Figure 1

Effect of epitope variation on recognition of peptide-pulsed targets by ML 857, using PBMCs obtained before seroconversion. (a) HPDIVIYQY-stimulated bulk CTL line recognizes autologous B lymphoblastoid cell line (BCL) targets pulsed with peptide HPDIVIYQY, but not infecting variant NPQIIIYQY. (b) NPEIIIYQY-stimulated bulk CTL line does not recognize autologous BCL targets pulsed with either peptide HPDIVIYQY or NPEIIIYQY. Recognition is defined as greater than 10% specific lysis of peptide-pulsed target cells by a bulk CTL line (see text for assay details).

Figure 2

Association between HIV-1 epitope–specific ELISPOT responses (see text for definition of an HIV-1 epitope–specific response) and levels of sex work in persistently HIV-1–seronegative Kenyan sex workers. HIV-1–specific ELISPOT responses are shown on the y axis as SFU/10⁶ PBMCs. Solid lines represent IFN-γ release in response to HIV-1 CTL peptide epitopes, and the dashed lines represent the IFN-γ response to R10 medium alone. Assay date is shown on the x axis, together with the reported number of daily clients and percentage of condom use. Stopping sex work completely was generally associated with loss of HIV-1–specific ELISPOT responses, demonstrated by ML 1192 (a) and ML 851 (b), although ML 1732 maintained a response for over a year after stopping sex work (c). A temporary break (≥2 months) from sex work was also associated with the loss of HIV-1–specific responses (ML 1437) (d), and responses were detected again 1–12 months after resuming sex work in ML 1250 (e), ML 1749 (f), and ML 851 (before retirement) (b). HIV-1–specific responses tended to be maintained in the absence of a break from sex work, shown by ML 1671 (g) and ML 887 (h).

Figure 3

Time to HIV-1 seroconversion after enrollment in the Pumwani sex worker cohort, 1983–1999.