HIV and aging as a model for immunosenescence.

Abstract

A of February 1997, 591,302 cases of acquired immunodeficiency syndrome (AIDS) had been reported in the United States; 10% of these were in persons aged 50 years or over, a proportion that has remained relatively stable since 1983 (1). Despite these significant numbers, this problem has received relatively little attention. Now that the number of pediatric AIDS cases is decreasing — the use of anti-retroviral drugs in the peripartum period reduces maternal-infant transmission — the relative proportion of infected adults should increase. Additionally, the absolute number of older persons with human immunodeficiency virus (HIV) infection is likely to grow. Sexual intercourse, not blood transfusion, is now the predominant mode of transmission of the virus in older adults (2). Seniors do not perceive themselves to be at risk for HIV infection (or are no longer concerned about contraception). Consequently, they are one-sixth as likely to use condoms during intercourse and one-fifth as likely to have been tested for HIV infection as individuals in their 20s (3). Finally, as new therapies become more widespread, HIVinfected persons will be living longer. Advancing age is, of course, a recognized risk factor for many infectious diseases. The more rapid progression of HIV in older persons was previously ascribed to associated comorbid diseases or to delayed diagnosis. Recent studies support both of these notions. In a retrospective casecontrol study, Skiest et al. (4) found that older HIV-positive patients had shorter AIDS-free interval, shorter survival, and more HIV-related and non-HIV-related comorbidity. They also had lower CD4 cell counts at the time of diagnosis, which the investigators ascribed to a lack of HIV awareness, but which also could be due to a more rapid loss of CD4 cells. Further, el-Sadr and Gettler (5) tested serum samples of 257 persons who died in Harlem Hospital, were over age 60, and had no history of HIV infection. Thirteen (5%) of the samples were HIV-positive. These data may not be generalizable (Harlem is a high HIV-incidence area and no samples from younger persons were used as controls), but they do out the need to consider HIV infection in older persons. The Centers for Disease Control's recommendation that routine HIV screening be offered to hospitalized patients between the ages of 15 and 54 years also might be short-sighted (6). Even in the absence of comorbidity, HIV infection progresses more rapidly in older persons (7-9). Darby et al. (9) studied HIV-infected hemophiliacs ranging in age from 8 months to 79 years; after a 10-year follow-up, both time without progressing to AIDS and survival were inversely associated with age at time of seroconversion (see Table 1). Because thymic atrophy also occurs after adolescence, these data are consistent with an immunological role. Recent studies on HIV ;;athogenesis show that there is a dynamic strugg'c between viral production and loss of CD4 T-cells. Tiitre are 10-10 new virions produced every day with a correspondingly high turnover of CD4 T-cells in HIV-infected individuals — on the order of 2 X 10/day (the circulating half-life of virus-infected cells is only 1.3 days). Because the regenerative capacity of the immune system is finite, it is believed that, during the course of infection, cell death eventually exceeds cell renewal, leading to loss of CD4 T-cells and subsequent immune deficiency (10,11). It is therefore logical that the age-associated acceleration in HIV progression is immunologically based. Five possible immunological mechanisms come to mind: with aging, more virus is produced; more CD4 T-cells are infected; the cells are destroyed more rapidly; the cells cannot be replaced as efficiently; or there is less effective anti-HIV immune activity, resulting in higher viral burden. There are data consistent with all five of these hypotheses and, as in much of aging, the actual reason may be multifactorial. First, HIV production is under the control of many cytokines; pro-inflammatory cytokines, such as interleukin 6 and tumor necrosis factor-a upregulate HIV production, whereas other cytokines, such as interleukin 10, downregulate it (12). Long-term prognosis is inversely proportional to the amount of virus in the blood, also referred to as the point (13). Could the set be higher in older persons? If so, could this be due to the age-related increase in interleukin 6 (14)? Are other cytokines involved as well? Second, HIV preferentially infects memory T-cells of both adults (15) and children (16); these cells are characterized by the presence of CD45RO, the low molecular weight isoform of the leukocyte common antigen family. CD4CD45RO memory T-cells develop from CD4CD45RA naive T-cells via a post-thymic differentiation pathway. Less than 20%