CD4+ T cells in HIV

Human immunodeficiency virus (HIV) is a member of the retrovirus family and progresses into AIDs after a period of time. AIDs is defined by a significant deficiency in T-cell count which causes a progressive failure of the immune system and allows life-threatening opportunistic infections and cancers to thrive. Infection with HIV occurs by the transfer of blood, semen, vaginal fluid, or breast milk. In order to slow the progression to AIDs, many people with HIV take antiretroviral therapy which combines a number of drugs that are designed to stop HIV from infecting cells: includes nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, and triple-nucleoside (or nucleotide) reverse transcriptase inhibitors (NRTIs) (1). HIV initially depletes the body’s CD4 T-cells and the point of this therapy is to boost the immune system back to normal to continue to fight the infection. However, 30% of patients with HIV who receive antiretroviral therapy fail to achieve a normal CD4⁺ T-cell count (2). This failure to achieve normal T-cell levels results in a steady decrease in T-cells to where, in less than 10 years, the count is below 500 (signifying AIDs) leaving the patient open to opportunistic infections and eventually death. Therefore it is necessary to study the reasons for this initial failure to reach normal T-cell counts with antiretroviral therapy in order to enhance its function.

HIV first infects CD4 T-cells, depleting the amount in the body. However, there is normally a period of time in which the T-cells regenerate in order to fight the infection. The balance of T-cells in the body is negatively regulated by interferon α (IFN-α) and evidence suggests that HIV increase the production of this interferon (3). This regulating interferon may promote apoptosis of uninfected CD4⁺ T cells by up-regulating expression of a death signal (TRAIL) and its death receptor (TRAIL receptor) (4). Therefore, the role of IFN-α may have important effects on CD4 T-cell populations in HIV patients.

A study by Sonia Fernandez at the School of Pathology and Laboratory Medicine in Australia looks at the effects of IFN-α on CD4 T-cell populations in HIV patients. They recruited HIV patients who have been receiving effective doses of antiretroviral therapy and measured the levels of CD 4 T-cells in the blood as well as levels of IFN-α. The patients were divided into low or high CD4 T-cell groups. Expression of markers of T-cell activation (HLA-DR), apoptotic potential (Fas), or aging (CD57) were assessed and it was found that the proportions of CD4⁺ T cells expressing HLA-DR or Fas were higher in patients with low CD4⁺ T-cell counts than in those with high counts such that the higher the levels of Fas and HLA-DR that are expressed, the lower the population of CD4+ T-cell count. The proportion of CD4⁺ T cells expressing CD57 did not differ between patients with low or high CD4⁺ T-cell counts. They left the cells in a culture for 72 hours and found that the proportions of CD4⁺ and CD8⁺ T cells that were apoptotic or preapoptotic was similar in patients with low and high CD4⁺ T-cell counts.

They then evaluated IFN-α activity to determine if it was an indicator of low CD4⁺ T-cell counts. They looked at the products that are stimulated by IFN-α (IF16-16, ISG56, and IF127) the CD4⁺ T cells of patients and healthy controls. Levels of IF16-16, ISG56, and IF127 were higher in patients with low CD4⁺ T-cell counts than in patients with high CD4⁺ T-cell counts and healthy controls. Levels of interferon-stimulated gene transcripts in patients with high CD4⁺ T-cell counts were similar to those in healthy controls. The levels of each of the INF-α stimulated products were compared in patients with low or high estimated CD4⁺ T-cell counts 10 years after antiretroviral therapy and found that results were similar to those observed with current CD4⁺ T-cell counts. This means that the levels of the IFN-α products haven’t changed after 10 years on therapy and therefore might have something to do with the decrease in T-cell counts.

However, no significant relationship was observed between the expression of INF-α and markers of T-cell activation or apoptosis. However, there was an association between the levels of IF127 in CD4⁺ T cells and the proportion of CD4⁺ T cells expressing Fas and the levels of ISG56 in CD4⁺ T cells and the proportion of CD4⁺ T cells expressing CD57. Therefore, the products of INF-α may be involved in the depletion of CD4 T cells rather than IFN-α itself.

They then observed the translocation of bacteria by measuring the levels of their products (LPS and 16SrDNA) through LPS’s receptor and activation marker, sCD14, and through antibody detection of LPS. The levels of LPS and 16SrDNA were similar in patients with low or high CD4⁺ T-cell counts. However, levels of sCD14 were higher in patients with low CD4⁺ T cells such that patients with high CD4 T cells would have lower levels of sCD14. Antibody detection of LPS was similar between patients with low and high CD4⁺ T-cell counts. Then, the researchers compared the levels of each LPS, 16SrDNA and sCD14 with the levels after 10 years with antiretroviral therapy and only high levels of sCD14 were associated with low CD4⁺ T-cell counts.

The researchers finally examined the CD4 T-cell markers for activation, aging, and apoptosis (HLA-DR, CD57, and Fas) and the indicators of translocation (LPS, 16SrDNA, and sCD14). Levels of sCD14 correlated with CD4⁺ T cells that express HLA-DR, antibodies against LPS correlated with CD4⁺ T cells that express Fas and antibodies against LPS correlated with CD4⁺ T cells that express CD57. This study examined the association of CD4⁺ T-cell recovery (HLA-DR activation expression) with markers of translocation and IFN-α and concluded that there were elevated levels of IFN-α in CD4⁺ T cells from with low CD4⁺ T-cell counts, whereas IFN-α expression in the patients with high CD4⁺ T-cell counts was similar to that in non-HIV controls. Therefore, controlling IFN-α in HIV patients may increase the number of CD4 T cells and therefore slow the progression to AIDs. However, this study did not find any correlations with IFN-α and markers of activation or apoptosis of T-cells (HLA-DR and Fas) thereby suggesting that the control of apoptosis of CD4 T cells by IFN-α is not through deactivation of T-cells or Fas induced apoptosis.

Primary Article

1) Fernandez, Sonia, et al. CD4⁺ T-Cell Deficiency in HIV Patients Responding to Antiretroviral Therapy Is Associated With Increased Expression of Interferon-Stimulated Genes in CD4⁺ T Cells J Infect Dis. (2011) 204 (12):1927-1935.

Secondary Refrences

1) Yeni PG, Hammer SM, Hirsch MS, et al. Treatment for adult HIV infection: 2004 recommendations of the International AIDS Society-USA Panel. JAMA, 2004;292:251-65.

2) Gazzola L, Tincati C, Bellistri GM, Monforte A, Marchetti G. The absence of CD4+ T cell count recovery despite receipt of virologically suppressive highly active antiretroviral therapy: clinical risk, immunological gaps, and therapeutic options. Clin Infect Dis 2009;48:328-37.

3) Lehmann C, Harper JM, Taubert D, et al. Increased interferon alpha expression in circulating plasmacytoid dendritic cells of HIV-1-infected patients. J Acquir Immune Defic Syndr 2008;48:522-30.

4) Herbeuval JP, Hardy AW, Boasso A, et al. Regulation of TNF-related apoptosis-inducing ligand on primary CD4+ T cells by HIV-1: role of type I IFN-producing plasmacytoid dendritic cells. Proc Natl Acad Sci U S A 2005;102:13974-9.