This study determined the prevalence and clinical correlates of CXCR4-using virus in a cohort of ART-naïve HIV-1 C-infected women in Botswana. Because previous studies suggested a much lower frequency of CXCR4-using virus in HIV-1C infection, we selected women with low CD4 cell counts for testing in order to increase the likelihood of identifying DM or X4 virus. Because some studies suggest that ART may select for DM or X4 virus, the prevalence of CXCR4-using virus was examined in ART-naïve women.
Nearly 15% of women with CD4 cell counts below 200 cells/mm3
harbored DM virus. By contrast, studies in subtype B-infected patients with similarly advanced HIV-1 disease show a prevalence of CXCR4-using virus of 50% or more2, 3, 5, 21, 22
. Previous studies among treatment-naïve patients infected with HIV-1C virus show a prevalence of DM virus of 0 to 30%. These studies were generally based on small numbers of patients in Africa, with the largest having 40 patients6–9, 11, 14, 15, 23–25
. One study of 174 HIV-1C-infected patients in India showed a prevalence of 3.5% for CXCR4-using virus in treatment-naïve patients who had a wide range of CD4 cell counts26
. Because our study focused on patients with lower CD4 cell counts, the prevalence of DM and X4 virus among HIV-infected patients in Botswana overall most likely is considerably lower than 15%. The relatively low frequency of CXCR4-using virus even among persons with advanced disease suggests that CCR5 antagonists such as maraviroc may be particularly useful in the treatment of HIV-1C infection. These data also support evaluating the role of CCR5 antagonists as agents for the prevention of HIV-1 transmission in areas of the world where HIV-1 C predominates.
The association of HIV-1 coreceptor usage and disease is well-established in HIV-1 subtype B infection but less so for other subtypes4, 27–29
. Because our study only examined HIV-1 coreceptor usage among patients within a narrow range of CD4 cell counts, it was not possible to assess fully the association between CD4 cell count and presence of CXCR4-using virus. Nevertheless, even among patients with CD4 counts below 200 cells/mm3
there was a significant trend towards higher prevalence of CXCR4-using HIV-1 among patients with the lowest CD4 counts (p=0.02).
In cross-sectional studies of subtype B-infected patients, CXCR4-using virus is detected in approximately 20% of treatment-naive patients but in up to 50% of treatment-experienced patients27, 29–32
. This difference suggests to some that ART selects for CXCR4-using viruses, independent of CD4 cell count. However, after adjusting for nadir CD4 cell count the association of ART and CXCR4 is no longer statistically significant33, 34
. In a cross-sectional study of 28 HIV-1C-infected patients, CXCR4-using virus was not detected in any ART-naïve patients but was found in 50% of ART-experienced patients. This finding led the authors to propose that ART exerts a greater effect on coreceptor usage in HIV-1C infection as compared to subtype B14
. In the current study, the majority of women with R5 virus at the start of ART remained R5 at the time of virologic failure; DM virus emerged in only 4 (19%) women. This rate is consistent with observations from natural history studies, in which DM or X4 virus emerged in 23% of patients over time22
This study has several limitations. As noted above, the inclusion only of women with low CD4 cell counts may have limited the ability to detect significant associations between coreceptor usage and other clinical factors. In addition, data were obtained from pregnant women only; gender and pregnancy, however, are not known to affect the emergence of CXCR4-using virus. The phenotypic assay used in the current study can detect minority CXCR4-using variants present at 1% to 5% of the population, depending on the plasma virus load. It is possible that a somewhat higher frequency of CXCR4-using virus would have been detected using the enhanced-sensitivity Trofile assay (Monogram BioSciences, South San Francisco, CA), which has a threshold of detection of 0.3% for CXCR4-using variants35
In summary, DM virus was readily detected in HIV-1C-infected women with advanced disease, but its prevalence was considerably lower than that reported in subtype B- or D-infected patients with similarly advanced disease36, 37
. Exposure to ART did not appear to be a major factor in emergence of CXCR4-using virus in the cohort studied here. Such knowledge is essential for an improved understanding of the biological and clinical differences between HIV-1 subtypes, and for the design of therapeutic agents and preventive vaccines targeted against the most prevalent HIV-1 subtype.