CD4+ T follicular helper (Tfh) cells are critical for the generation of humoral immune responses to pathogenic infections, providing help for B cell development, survival, and affinity maturation of Abs. Although CD4+ Tfh cells are reported to accumulate in HIV or SIV infection, we found that germinal center Tfh cells, defined in this study as CXCR5+ PD-1 HIGH CD4+ T cells, did not consistently accumulate in chronically SIV-infected rhesus macaques compared with those infected with less pathogenic simian HIV, vaccinated and SIVmac-challenged, or SIVmac-infected Mamu-A* 01+ macaques, all of which are associated with some control of virus replication and slower disease progression. Interestingly, CXCR5+ PD-1 HIGH Tfh cells in lymphoid tissues were eventually depleted in macaques with AIDS compared with the other cohorts. Chronic activation and proliferation of CXCR5+ PD-1 HIGH Tfh were increased, but PD-L2 expression was downregulated on B cells, possibly resulting in germinal center Tfh cell apoptosis. Together, these findings suggest that changes in CXCR5+ PD-1 HIGH Tfh cells in lymph nodes correlate with immune control during infection, and their loss or dysregulation contribute to impairment of B cell responses and progression to AIDS.