4 per 1000 person-years. This

is less than half of the incidence rate in developed countries before the introduction of HAART [3], but as the trial allocation was concealed, it seems unlikely that this would explain the group difference in rates of all-cause pneumonia. Although the authors regarded the reduced mortality among vaccinees as a chance finding, it remains possible that this was in fact a ‘true’ finding, and that PPV-23 may have unknown beneficial effects on the immune system. This setting is quite different from the situation in the developed world and so the conclusions about the efficacy of PPV-23 should be extrapolated to other settings with caution. In developed countries, with widespread use of HAART, most studies have shown that HAART has had the most consistent effect on check details reducing the incidences of pneumonia and pneumococcal

disease. Without access to HAART, most HIV-infected patients have much higher degrees of immunosuppression, serological PD0325901 datasheet responses to PPV-23 are poorer and the vaccine has less opportunity to be effective. Therefore, access to HAART and geographical location may contribute to the variation in PPV-23 effectiveness in different settings. There are a variety of ways in which HIV may disrupt the immune response to PPV-23. Although HIV does not directly target B cells, B-cell numbers are reduced in HIV-infected individuals and HIV infection is associated with several B-cell abnormalities including phenotypic changes, B-cell homing process disturbances, induction of apoptosis in B-cell populations, clonal deletion of B-cell populations, polyclonal B-cell activation, increased B-cell malignancy and hypergammaglobulinaemia [46]. Additionally, HIV proteins may directly interfere with antibody maturation. For example, the HIV protein glycoprotein 120 (gp120) can suppress the gene family VH3 and the HIV protein Nef interferes with immunoglobulin class shift [27,47]. The antibody response to PPV is thought to be derived from B cells expressing the VH3 gene family, and the suppression of VH3 in HIV-infected

individuals can be reduced by HAART Idoxuridine [13]. Initiation of HAART also results in significant increases in the populations of naïve and resting memory B cells, both of which are essential for generating adequate humoral immunity [48]. This may suggest that immune reconstitution by HAART has an effect on vaccine effectiveness that is in excess of the contribution from higher CD4 cell counts and lower viral loads. The increasing amount of uncertainty regarding the effectiveness of PPV-23, not only in HIV-infected patients, as highlighted in this review, but also in other populations [49,50], might suggest the need for more rigorous trials. However, as new and potentially more immunogenic vaccines are being developed, it is doubtful whether anyone will be willing to conduct such trials.