Older age and immune response to CMV affect CD4 cell recovery after starting HIV therapy

Older age and a strong immune response to CMV infection adversely affect CD4 cell count recovery in patients taking antiretroviral therapy, French investigators report in the September 24^th edition of AIDS. 

“HIV appears to amplify immune aging,” write the authors. “Under ART [antiretroviral therapy] age as well as the mounting of robust anti-CMV (cytomegalovirus] T-cell responses independently alter T-cell reconstitution in treated patients.”

The diseases of aging are an increasingly important cause of serious illness and death in patients with HIV. This is partly due to the advancing age of the HIV-infected population.

However, the increased immune activation and inflammation that accompanies chronic HIV infection are also thought to have an important role in the development of illnesses such as cardiovascular disease, osteoporosis, and some cancers.

Viral co-infections are common in patients with HIV, and CMV infection is present in between 75% and 90% of HIV-positive patients, with earlier research showing that responses to this infection can be accompanied by an aging of the immune system.

Investigators from Paris therefore designed a study to determine the effect of age and CMV infection on CD4 cell count recovery in patients taking HIV treatment.

They analysed blood samples obtained from HIV-positive patients aged between 25 and 60 years who were not yet taking antiretroviral therapy. Blood samples were also obtained from individuals aged between 25 and 81 years who were receiving HIV treatment. For the purposes of comparison, samples were also obtained from young (18 to 25 years), middle aged (25 to 55 years) and elderly (75 to 96 years) HIV-negative controls.

After comparing the immune profiles of the HIV-infected patients and the HIV-negative controls, the investigators established that the aging of the immune system seen in HIV-positive patients was characterised by a decline in naïve T-cells.

“Altogether, the comparison of elderly donors and untreated HIV-infected progressors stresses that the decline in naïve T cells…represents a robust immunologic manifestation of the parallel between aging and HIV disease progression,” comment the investigators.  “Most HIV-infected individuals with a CD4 T-cell count below 200 cells/mm³ were comparable to elderly donors (i.e. mean of 85 years) when considering naïve CD4 and CD8 T-cell frequencies.”

The investigators then compared the immune profiles of elderly HIV-positive patients (aged over 65) who had a good CD4 cell response to HIV therapy with the immune profiles of middle-aged HIV-infected patients.

Although the absolute CD4 cell counts of the two groups were comparable, the elderly patients had fewer naïve CD4 and CD8 cells than the middle-aged patients.

“We found…strong inverse correlations between age and naïve CD4 (p < 0.0001) or CD8 (p < 0.0001) T-cells in treated HIV-infected donors,” write the authors. “The recovery of naïve T cells…are thus limited by advanced age.”

Further analysis showed that HIV itself (p = 0001) also had an independent effect on the frequency of naïve T cells.

“Overall, this indicates that HIV amplifies the adverse effect of age on naïve T-cell production, even in the context of ART,” comment the authors.

They emphasise that CD4 cell recovery in older patients is not equivalent to that seen in younger patients.

The authors believe this finding is especially important “since distinct drug regimens may thus be envisaged according to age in order to achieve optimal T-cell reconstitution…future studies will need to asses the effects of regimens combining antiretroviral and immunomodulatory drugs in old HIV-infected patients in order to design the most adapted treatments for this population.”

The study also showed that HIV-positive patients also had a greater CMV-specific immune response than the HIV-negative controls. This finding was especially obvious for patients taking antiretroviral therapy (p < 0.001). Moreover, older HIV-positive patients had the highest magnitude of CMV-specific T-cell response of all (p < 0.0001).

When the investigators focused on patients taking HIV therapy, they found that individuals with a strong response to CMV had significantly lower CD4 cell counts and a CD4 cell count recovery from nadir compared to individuals with a lower CMV response (p = 0.019).

“The mounting of a strong anti-CMV T-cell responses may mobilize a significant part of the [immune] resources, which may result in lower naïve T-cells numbers in the absence of adequate T-cell renewal capacity, thus altering T-cell reconstitution upon ART,” explain the investigators. “Loss of naïve T cells with CMV-mediated memory…may provide potential mechanistic insights underlying the association between CMV infection and more rapid HIV disease progression.”

The investigators conclude that their findings are “important for the long-term clinical management of the aging HIV-infected population.”

Appay V et al. Old age and anti-cytomegalovirus immunity are associated with altered T-cell reconstitution in HIV-1-infected patients. AIDS 25: 1813-22, 2011 (click here for the free abstract).