Background:  One hypothesis of T-cell dysfunction is abnormal maturation of HIV-specific cells. We have seen that some antiretroviral-treated patients with multidrug-resistant HIV maintain low-level viremia and have robust HIV-specific CD4⁺ and CD8⁺ T-cell responses.Given these observations, we hypothesize that these patients may be immunologically controlling viral replication in a manner analogous to long-term non-progressors, and that these 2 groups would have immunologic maturation patterns distinct from those with progressive HIV disease.

Methods:  We developed a flow cytometry panel to define memory and effector CD8⁺ T-cell phenotypes. PBMC were stimulated with HIV Gag peptide pools. Interferon-g secretion and cell surface marker expression was quantified.We analyzed 50 patients enrolled in the SCOPE cohort. The patient groups were:  long-term non-progressors (LTNP), patients with with progressive HIV disease and poor virologic control (progressors), patients responding virologically to  HAART (plasma HIV RNA <75 copies/mL) (suppressors), and patients with partially controlled viremia on antiretroviral therapy (PCAT), defined as the presence of drug-resistant HIV and plasma HIV RNA levels <10,000 copies.

Results:  The median CD4 count of the cohort was 437 (10 to 1430) and median viral load was 51,955 (<50,000 to 676,000).The LTNP and PCAT groups had higher numbers and percentages of  Gag-specific CD4⁺ and CD8⁺ T cells than progressors and suppressors. Gag-specific CD8⁺ T cells within the LTNP and PCAT patients were shifted toward a late effector phenotype(CCR7^-CD45RA⁺CD27^-CD28^-) compared with progressors or suppressors. In contrast, Gag-specific CD4⁺ T cells were primarily shifted toward a late effector or effector memory (CCR7^-CD45RA^-CD27^±CD28^±) phenotype in the PCAT.

Conclusions:  Many different immune parameters are responsible for improved virologic response.The presence of a larger number of late effector HIV-specific CD4⁺ and CD8⁺ T cells appears to be associated with improved virologic control in both untreated (LTNP) and treated (PCAT) patients, suggesting these cells contribute to the ability of these patients to control viremia. Patients controlling drug-resistant HIV (PCAT) also have a larger number of effector memory and late effector HIV-specific CD4⁺ T cells compared with all groups. This observation may be due to MDR virus interacting with maturation of CD4⁺ T cells in a manner different from wild-type HIV.

Keywords: maturation; T cell; MDR virus