Aging and Infectious Diseases: Workshop on HIV Infection and Aging: What Is Known and Future Research Directions

Abstract

Highly active antiretroviral treatment has resulted in dramatically increased life expectancy among patients with HIV infection who are now aging while receiving treatment and are at risk of developing chronic diseases associated with advanced age. Similarities between aging and the courses of human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome suggest that HIV infection compresses the aging process, perhaps accelerating comorbidities and frailty. In a workshop organized by the Association of Specialty Professors, the Infectious Diseases Society of America, the HIV Medical Association, the National Institute on Aging, and the National Institute on Allergy and Infectious Diseases, researchers in infectious diseases, geriatrics, immunology, and gerontology met to review what is known about HIV infection and aging, to identify research gaps, and to suggest high priority topics for future research. Answers to the questions posed are likely to help prioritize and balance strategies to slow the progression of HIV infection, to address comorbidities and drug toxicity, and to enhance understanding about both HIV infection and aging.

Immunosenescence and hurdles in the clinical management of older HIV-patients

“…25 Coinfections and pro-inflammatory pattern HIV itself, especially before the start of HAART, herpesviridae, in particular cytomegalovirus (CMV), and hepatitis viruses cause a prolonged stimulus to the immune system, reducing in particular the capability of proliferation of the T cells and depleting T-cells receptor (TCR) repertoire. 7,8,26 CMV causes a lifelong infection able to produce continuous antigenic stimulation thanks to most of viral proteins (751 unique CMV proteins) in infected cells. 27 This antigen burden is responsible for a more restricted T-cells repertoire and cause the accumulation of terminally differentiated T-cells, a process called "memory inflation."…”

“…38 Moreover, the human T-cell compartment lose CD28 expression on CD8 T-cell during the shift from central to effector memory cells. 26,34 CD28C has a central role in the proliferation of CD8C T-cells as one of the main co-stimulator of TC cell response during the antigen presentation between APCs and T-cells (in conjunction with TCR recognition by peptide bound to host MHC proteins on APCs). 26,29,38 In addition to the loss of CD28, CD8 T-cells express other markers of exhaustion, replicative senescence (mediated by upregulation of p21 and p16, as explained above), or terminal differentiation in the context of aging (such as PD-1, CD57, or KLRG1); moreover, they have increased production of IL6 and TNF-a 28 and reduced length of telomerases.…”

“…26,34 CD28C has a central role in the proliferation of CD8C T-cells as one of the main co-stimulator of TC cell response during the antigen presentation between APCs and T-cells (in conjunction with TCR recognition by peptide bound to host MHC proteins on APCs). 26,29,38 In addition to the loss of CD28, CD8 T-cells express other markers of exhaustion, replicative senescence (mediated by upregulation of p21 and p16, as explained above), or terminal differentiation in the context of aging (such as PD-1, CD57, or KLRG1); moreover, they have increased production of IL6 and TNF-a 28 and reduced length of telomerases. 8,28,29,38 Recent studies have reported that the senescence phenotype in both CD8 effector memory and CD4 T-cells is strongly associated with irregular signaling via the p38 MAP kinase.…”

“…Despite these similarities, antiviral CD8C memory T-cell populations typically persist at relatively constant levels over time, whereas virus-specific CD4C memory T-cells decrease in frequency; this combination provokes a reduction in CD4:CD8 ratio that is enhanced both in aging and in HIV infection. 26,29,38 Antigen persistence is required for long-term maintenance of CD4C memory T-cells. 43 Memory T cells can be divided into 2 main subsets, central memory (TCM; cells with high levels of CD62L and CCR7) and effector memory cells (TEM; cells with low levels of CD62L and CCR7, which actively expresses effector functions and traffics to peripheral rather than secondary lymphoid tissues), based on expression of homing and chemokine receptors involved in preferential trafficking to secondary lymphoid organs or peripheral sites, respectively.…”

Coronary Artery Disease in Patients with HIV Infection

“…Currently, CVD is the second most frequent cause of death among HIV patients, with the first being cancer [2]. The subclinical makers of atherosclerosis, such as carotid, femoral, or iliac intima-media thickness are consistently greater and progress earlier among the HIV-positive population than among the general population [3,4].…”