Incomplete Recovery of Pneumococcal CD4 T Cell Immunity after Initiation of Antiretroviral Therapy in HIV-Infected Malawian Adults

Abstract

HIV-infected African adults are at a considerably increased risk of life-threatening invasive pneumococcal disease (IPD) which persists despite antiretroviral therapy (ART). Defects in naturally acquired pneumococcal-specific T-cell immunity have been identified in HIV-infected adults. We have therefore determined the extent and nature of pneumococcal antigen-specific immune recovery following ART. HIV-infected adults were followed up at 3, 6 and 12 months after initiating ART. Nasopharyngeal swabs were cultured to determine carriage rates. Pneumococcal-specific CD4 T-cell immunity was assessed by IFN-γ ELISpot, proliferation assay, CD154 expression and intracellular cytokine assay. S. pneumoniae colonization was detected in 27% (13/48) of HIV-infected patients prior to ART. The rates remained elevated after 12 months ART, 41% (16/39) (p = 0.17) and significantly higher than in HIV-uninfected individuals (HIVneg 14%(4/29); p = 0.0147). CD4+ T-cell proliferative responses to pneumococcal antigens increased significantly to levels comparable with HIV-negative individuals at 12 months ART (p = 0.0799). However, recovery of the pneumococcal-specific CD154 expression was incomplete (p = 0.0015) as were IFN-γ ELISpot responses (p = 0.0040) and polyfunctional CD4+ T-cell responses (TNF-α, IL-2 and IFN-γ expression) (p = 0.0040) to a pneumolysin-deficient mutant strain. Impaired control of pneumococcal colonisation and incomplete restoration of pneumococcal-specific immunity may explain the persistently higher risk of IPD amongst HIV-infected adults on ART. Whether vaccination and prolonged ART can overcome this immunological defect and reduce the high levels of pneumococcal colonisation requires further evaluation.

Long‐term immune responses and comparative effectiveness of one or two doses of 7‐valent pneumococcal conjugate vaccine (PCV7) in HIV‐positive adults in the era of combination antiretroviral therapy

“…In our multivariate analysis, we show that receipt of cART becomes a significant predictor of significant immune responses in the fourth and fifth years but not in the second and third years; that is, cART takes time to have an effect. This finding is consistent with studies showing persistent defects in pneumococcal antigen specific immunity by IFN-gamma ELISpot, T-cell proliferation, CD154 expression and intracellular cytokine assays despite 12 months of cART and persistently higher S. pneumoniae carriage rates despite 18 months of cART [6,8]. As the extent of immune recovery at 12 months was greater than at three or six months after cART, the capacity for ongoing reconstitution over time and subsequent effect thereof on immunogenicity and induced-immunological memory of PCV is implied [8].…”

“…This finding is consistent with studies showing persistent defects in pneumococcal antigen specific immunity by IFN-gamma ELISpot, T-cell proliferation, CD154 expression and intracellular cytokine assays despite 12 months of cART and persistently higher S. pneumoniae carriage rates despite 18 months of cART [6,8]. As the extent of immune recovery at 12 months was greater than at three or six months after cART, the capacity for ongoing reconstitution over time and subsequent effect thereof on immunogenicity and induced-immunological memory of PCV is implied [8]. The late effects of cART could also be inferred from the similar responses found for immunologically AIDS patients immunized immediately compared to those who had received cART for 6 to 12 months before vaccination [62].…”

“…This risk may be related to HIV-related accelerated senescence of immune repertoire and loss of memory B cells prior to viral suppression and the relative dysregulation of the reconstituted but incompletely restored immune system following antiretroviral therapy [4–8]. Consequently most authorities, including the Advisory Committee on Immunization Practices of the US Centers for Disease Control and Prevention, the World Health Organization (WHO), the European AIDS Clinical Society and the British HIV Association, recommend pneumococcal vaccination for all HIV-positive adults regardless of immune status [9–13].…”

T FH in HIV Latency and as Sources of Replication-Competent Virus

“…The number of functional circulating T FH is decreased in untreated HIV+ subjects, and T FH numbers and function slightly recover in treated HIV+ subjects [25]. However, T FH function is still incomplete and HIV+ subjects still have functional impairments [19] and poor vaccine responses [56, 57]. T FH function has also been found to be crucial for subsequent vaccine responses in treated HIV+ subjects, as responses to flu vaccination were directly dependent on the ability of T FH to proliferate, express ICOS, and produce IL-21 [58].…”

Staphylococcus aureusandStreptococcus pneumoniaeinteraction and response to pneumococcal vaccination: Myth or reality?

“…64 Indeed, pneumococcal-specific CD4 C T cells have been found to return to normal levels following anti-retroviral therapy. 65 This suggests that the interaction between the S. aureus and S. pneumoniae may be CD4…”