Background:  While the advent of HAART has resulted in the ability of HIV-infected individuals to control HIV replication, we still do not know whether the immune system in these individuals becomes entirely normal over time.

Methods:  We studied 29 HIV-infected individuals with uncontrolled HIV (progressors), 21 HAART-suppressed individuals (HS), and 7 HIV-uninfected individuals (HIV^neg).  Cryopreserved peripheral blood mononuclear cells (PBMC) from all subjects were stained with antibodies to CD3, CD8, CD27, CD28, CD45RA, CCR7, and intracellular Ki67.

Results:  In progressors, a significantly decreased proportion of CD8⁺ T cells are of a “naïve” phenotype (CD45RA⁺CCR7⁺CD27⁺CD28⁺) compared to HIV^neg individuals (16 vs 34%, p = 0.008) with a concomitant increased proportion with a late differentiated (CD45RA^–CCR7^–CD27^–CD28^–) phenotype (17 vs 4%, p = 0.0004). Despite effective treatment with HAART, HS individuals have a similar proportion of naive CD8⁺ T cells as progressors (13 vs 16%, p = 0.30) and diminished compared to HIV^neg individuals (13 vs 34%, p = 0.004). Furthermore, the increase of late differentiated CD8⁺ T cells seen in progressive infection persists in HS individuals (9 vs 17%, p = 0.27) and is increased compared to HIV^neg individuals (9 vs 4%, p = 0.009). Analysis of the proliferation status of the different phenotypes of CD4⁺ and CD8⁺ T cells reveals that, in progressors and HS individuals, CD8⁺ late differentiated T cells had comparable levels of Ki67 expression, which was increased compared to HIV^neg controls (p = 0.03 and p = 0.02, respectively). And conversely, progressors and HS individuals had lower levels of Ki67 in naïve subsets compared to HIV^neg individuals (p = 0.003 and p = 0.01, respectively).  Similar patterns of increased proportions of cells with an effector phenotype and decreased proportions with a naïve phenotype are also seen in the CD4⁺ T cell population.

Conclusions:  This study reveals that, despite durable control of viral replication with HAART, T cell phenotype remains abnormal.  Increased proportions of highly differentiated CD4⁺ and CD8⁺ T cells persist and these phenotpyes are associated with high levels of proliferation, which may account for their increased numbers.  Similarly, a decreased frequency of naïve T cells also persists, with decreased proliferative capacity.  These abnormalities are also hallmarks of human aging, and may represent a limitation of effective HAART therapy.