Susan Plaeger

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

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.

Early Prognostic Indicators in Primary Perinatal Human Immunodeficiency Virus Type 1 Infection: Importance of Viral RNA and the Timing of Transmission on Long-Term Outcome

The time of perinatal human immunodeficiency virus type 1 (HIV-1) transmission and the pattern of early plasma viremia as predictors of disease progression were evaluated in infected infants followed from birth. Cox proportional hazards modeling demonstrated that a 1-log higher HIV-1 RNA copy number at birth was associated with a 40% increase in the relative hazard (RH) of developing CDC class A or B symptoms (P = .004), a 60% increase in developing AIDS (P = .01), and an 80% increase in the of risk death (P = .023) over the follow-up period of up to 8 years. The peak HIV-1 RNA copy number for infants during primary viremia was also predictive of progression to AIDS (RH, 9.9; 95% confidence interval [95% CI], 1.8-54.1; P = .008) and death (RH, 6.9; 95% CI, 1.1-43.8; P = .04). The results indicate that high levels of HIV-1 RNA at birth and during primary viremia are associated with early onset of symptoms and rapid disease progression to AIDS and death in perinatally infected children.

Two Double-Blinded, Randomized, Comparative Trials of 4 Human Immunodeficiency Virus Type 1 (HIV-1) Envelope Vaccines in HIV-1—Infected Individuals across a Spectrum of Disease Severity: AIDS Clinical Trials Groups 209 and 214

The potential role of human immunodeficiency virus type 1 (HIV-1)-specific immune responses in controlling viral replication in vivo has stimulated interest in enhancing virus-specific immunity by vaccinating infected individuals with HIV-1 or its components. These studies were undertaken to define patient populations most likely to respond to vaccination, with the induction of novel HIV-1-specific cellular immune responses, and to compare the safety and immunogenicity of several candidate recombinant HIV-1 envelope vaccines and adjuvants. New lymphoproliferative responses (LPRs) developed in <30% of vaccine recipients. LPRs were elicited primarily in study participants with a CD4 cell count >350 cells/mm(3) and were usually strain restricted. Responders tended to be more likely than nonresponders to have an undetectable level of HIV-1 RNA at baseline (P=.067). Induction of new cellular immune responses by HIV-1 envelope vaccines is a function of the immunologic stage of disease and baseline plasma HIV-1 RNA level and exhibits considerable vaccine strain specificity.

Shipment Impairs Lymphocyte Proliferative Responses to Microbial Antigens

ABSTRACT Lymphocyte proliferation assays (LPAs) are widely used to assess T-lymphocyte function of patients with human immunodeficiency virus infection and other primary and secondary immunodeficiency disorders. Since these assays require expertise not readily available at all clinical sites, specimens may be shipped to central labs for testing. We conducted a large multicenter study to evaluate the effects of shipping on assay performance and found significant loss of LPA activity. This may lead to erroneous results for individual subjects and introduce bias into multicenter trials.

Clinical Immunology and Traditional Herbal Medicines

The use of herbs to treat illness has its roots in an ancient holistic healing tradition that originated in Asia more than 3,000 years ago (10). Largely discounted by 19th and 20th century practitioners of Western medicine, healing practices incorporating herbal remedies, such as traditional Chinese medicine (TCM), Japanese Kampo, and Indian Ayurveda, are rapidly gaining acceptance in the West as we enter the 21st century. Herbal medicines are complex mixtures of minimally processed medicinal plants (e.g., plant parts that are boiled to make a tea). In conjunction with other components of traditional healing philosophies, such as acupuncture or massage, herbal medicines are used to treat a large range of symptoms and ailments, including liver disease, asthma, and other immune problems, menstrual problems, colds, headaches, and various cancers.

Pneumococcal and influenza immunization and human immunodeficiency virus load in children

Objective. HIV‐infected children receiving influenza vaccine, pneumococcal vaccine and both vaccines concurrently were studied to examine the effect of immunization on plasma HIV viral load. Methods. Thirteen children received immunizations: pneumococcal vaccine, 5; pneumococcal and influenza vaccines, 7; and influenza vaccine, 1. Most patients (12 of 13) were receiving combination reverse transcriptase inhibitor antiretroviral therapy without protease inhibitors at the time of immunization. Baseline plasma HIV RNA was determined 1 month prior (11 of 13), 2 weeks prior (12 of 13) and on the day of immunization (12 of 13). Plasma HIV RNA was assayed at 2 weeks (11 of 13), 4 weeks (12 of 13) and 3 months (5 of 13) after immunization. T cell activation markers (HLA‐DR+, CD38+ and CD45RO+, CD28+) were examined for both CD4+ and CD8+ lymphocytes on the day of immunization and 2 weeks after immunization for 11 children. Results. Only one child developed a >0.5‐log increase in viral load at any time after immunization. There was no correlation between an increase in viral load and antibody response to pneumococcal vaccine. At least one activation marker increased (>10%) for two children receiving pneumococcal vaccine and two children receiving pneumococcal and influenza vaccines. One of these children experienced an increase in viral load. Conclusion. Immunization with pneumococcal and influenza vaccines, alone or in combination, is rarely associated with a significant increase in HIV plasma RNA in children receiving combination antiretroviral therapy.

Immunologic activation during pregnancy: serial measurement of lymphocyte phenotype and serum activation molecules in HIV-infected and uninfected women

Immunologic alterations occur during pregnancy, but the effect of pregnancy on HIV infection is controversial. We characterized some of the immunologic alterations with potential to influence HIV disease in 99 infected and 46 uninfected women during pregnancy and up to 6 months post-partum. Immunophenotyping to quantitate the major lymphocyte subsets and determine expression of activation and adhesion molecules on T cells was performed using 3-color staining and laser flow cytometry. Serum neopterin, beta 2-microglobulin, and tumor necrosis factor-alpha (TNF alpha) were quantitated using commercial immunoassays. HIV + pregnant women were compared to uninfected pregnant subjects and to reference ranges established on healthy, HIV-seronegative non-pregnant female controls. Both CD4 and CD8 T cell subsets were increased in HIV-negative pregnant women compared to non-pregnant controls. In HIV-infected pregnant women, CD4 T cells were low and CD8 cells were elevated compared to HIV-negative pregnant and non-pregnant women. Levels of subsets were stable during pregnancy and postpartum in both groups of women. Evidence of peripheral immune activation was found during the later stages of pregnancy. Increases in HLA-DR and CD38 activation antigens on CD8 cells, serum neopterin and beta-2-microglobulin were seen during pregnancy in HIV-negative women. These correlates of immune activation were increased in HIV-infected pregnant women and increased further during pregnancy, paralleling changes seen in uninfected pregnant women. These immunologic alterations may directly or indirectly enhance viral replication, impacting the long-term course of HIV disease.

Antigen-Specific Production of RANTES, Macrophage Inflammatory Protein (MIP)-1α, and MIP-1β In Vitro Is a Correlate of Reduced Human Immunodeficiency Virus Burden In Vivo

RANTES (regulated on activation, normal T expressed and secreted), macrophage inflammatory protein (MIP)-1alpha, and MIP-1beta are human immunodeficiency virus (HIV) suppressor factors by virtue of their ability to compete with HIV for access to cell surface R5. Their ability to block HIV infection in vitro is unequivocal; however, their role as HIV suppressor factors in vivo is not firmly established. We therefore conducted a study to test the hypothesis that production of these factors in vitro was a correlate of decreased virus burden in vivo. Moreover, we asked whether higher beta chemokine production could be demonstrated with cells from people who are R5D32 heterozygotes, compared with people who are R5 wild-type homozygotes. Our data support the thesis that RANTES, MIP-1alpha, and MIP-1beta production is associated with decreased in vivo virus load. Moreover, enhanced production of these factors may be explained in part by the genetic background of the host.

Defective Virus Drives Human Immunodeficiency Virus Infection, Persistence, and Pathogenesis

Many aspects of the human immunodeficiency virus (HIV) life cycle are well understood, yet a key paradox remains. The primary targets for HIV are resting CD4 T lymphocytes that are not permissive to HIV replication unless activated by some external and independent event. Numerous mechanisms for this

Decreased CD8 Cell-Mediated Viral Suppression and Other Immunologic Characteristics of Women Who Transmit Human Immunodeficiency Virus to Their Infants

CD8 T cell function, lymphocyte surface phenotype, serum markers of immunologic activation, and viral burden were assessed in 75 human immunodeficiency virus (HIV)-infected pregnant women, including 9 who transmitted infection to their infants. Serial studies during and after pregnancy showed no significant differences in levels of cell-surface or serum activation molecules in transmitting compared to nontransmitting mothers, with the exception of a postpartum increase in tumor necrosis factor alpha in transmitting women. The transmitting women had a median plasma viral load of 65,516 RNA copies/mL at delivery versus 5139 in nontransmitting women. During the third trimester, the CD8 cells of 81% of the nontransmitting and 44% of the transmitting mothers suppressed HIV production in vitro by >50%. Women with <50% suppression had a 3.4 times greater risk of transmitting HIV to their infants. CD8 suppression and viral load were interrelated, but when either CD4 percent or AZT use was controlled for, suppression was still significant.