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.
Highlights
Invasive pneumococcal disease (IPD), in the form of pneumonia, bacteraemia and meningitis is a leading cause of mortality worldwide [1,2]
We have reported that pneumococcal–specific T and B-cell immunity is compromised in HIVinfected Malawian individuals, where there is a high frequency of pneumococcal exposure [11,12]
We show no change in the proportion of naive CD4+ T cells (CCR7+CD45RA+)[21,22] between 0 and 6 months ARTmediated immune reconstitution but that this subset had further increased by 12 months (Figure 1B, p = 0.0001), to levels even higher to those seen in HIV–uninfected individuals
Summary
Invasive pneumococcal disease (IPD), in the form of pneumonia, bacteraemia and meningitis is a leading cause of mortality worldwide [1,2]. Reconstitution of immunity in general occurs following initiation of antiretroviral therapy (ART) [13,14], IPD is still 30 times greater in HIV positive persons on ART compared to uninfected individuals [15,16] This suggests that following ART, reconstitution of immunity specific to S. pneumoniae may be incomplete. In a crosssectional study, we have recently shown striking increases in pneumococcal colonization with a broad range of serotypes during the progression of HIV infection in adults [17] These were associated with dynamic changes in peripheral pneumococcalspecific Th1 IFN-c immunity which together with these high levels of colonisation did not appear to fully resolve during immune reconstitution with ART. We have investigated the impact of ART on naturally-acquired CD4 T-cell mediated immunity to pneumococcal protein antigens in a prospective longitudinal study of otherwise healthy HIV-infected Malawian adults, using a wider array of functional assays to map out the kinetics and the degree of immune reconstitution, and their relationship to nasopharyngeal carriage of S. pneumoniae
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