Recent studies have revealed important clues as to why a small minority of HIV-infected people have remained healthy for many years without loss of immune function, according to researchers at the National Institute of Allergy and Infectious Diseases (NIAID) and their colleagues.
As reported in the Jan. 26, 1995 The New England Journal of Medicine, the investigators found that 15 HIV-infected volunteers with nonprogressive HIV disease had very low levels of HIV in their blood and lymph nodes; however, viral replication was persistent. The internal structure of these individuals' lymph nodes, unlike those of most people with HIV infection, appeared essentially undamaged, and the volunteers' immune function remained virtually unimpaired.
Cohort studies of HIV-infected individuals in the United States suggest that approximately 5 percent of these people can be characterized as "long-term non-progressors,"" says Giuseppe Pantaleo, M.D., of NIAID's Laboratory of Immunoregulation (LIR) and lead author of the paper. "Although we do not know precisely why these individuals are able to contain the virus, our data suggest that this phenomenon is associated with the maintenance of the integrity of the lymphoid tissues and with less virus-trapping in the lymph nodes than seen in other HIV-infected individuals. In addition, in the long-term non-progressors whom we studied, the immune response was relatively intact and appeared to control substantially, but not completely, HIV replication and the spread of the virus."
These findings suggest that low-level, persistent HIV replication may not necessarily be associated with disease progression if efficiently controlled over time," says Anthony S. Fauci, M.D., director of NIAID and LIR chief. "A further understanding of the relative contributions to non-progressive HIV disease of host factors such as the immune system and of virologic factors such as less virulent strains of the virus may prove critical to our understanding of AIDS pathogenesis and to the development of new vaccines and treatments for HIV infection."
The investigators defined long-term non-progressors as individuals who had been HIV-infected for seven or more years, had stable CD4+ T cell counts of 600 or more cells per cubic millimeter (mm3) of blood, no HIV-related diseases and no previous antiretroviral therapy. CD4+ T cells are the critical immune system cells targeted by HIV and typically depleted during the course of HIV infection.
Of the 15 long-term non-progressors in the study, seven came from the NIAID-supported Multicenter AIDS Cohort Study, which includes gay and bisexual men seen every six months since 1984. Four came from the San Francisco Cohort Study, a group of homosexual men recruited in the late 1970s for studies of hepatitis B. Another four came from an ongoing study at NIAID that examines the lymph nodes of HIV-infected individuals at various stages of infection. Of the 15 people, 13 had been infected for at least 10 years and all 15 had high counts of CD8+ T cells. No particular patterns of HLA, the "self" molecule on the surface of human cells recognized by the immune system, were observed among the participants.
For comparison, the researchers also examined 18 HIV- infected people enrolled in the NIAID lymph node study who had various degrees of disease progression. These people included three individuals with CD4+ T cell counts above 500/mm3, 11 with counts from 200 to 500 cells/ mm3 and four with counts below 200/mm3.
The investigators performed lymph node biopsies on 14 of the 15 long-term non-progressors and found that the organs were remarkably well-preserved. In one individual infected for 11 years, for example, lymph node samples from 1984 and 1993 were essentially identical. In contrast, lymph node samples taken from the 18 individuals in the control group showed patterns of deterioration typical of progressive HIV infection.
The investigators found various amounts of HIV trapped in the networks of follicular dendritic cells in the lymph nodes of 14 long-term non-progressors. The amounts of virus were less than the amounts seen in the individuals with progressive disease and paralleled the presence of lymph node structures called germinal centers, hot spots of cell proliferation and immune activity. Virtually no virus was detected in lymph nodes of five individuals with few or no evident germinal centers.
"The lack of virus-trapping in long-term non-progressors probably reflects the relatively non-reactive state of their lymphoid tissues, as compared to those with progressive disease, whose immune systems are chronically activated," says Dr. Fauci.
Using a sensitive technique called polymerase chain reaction, the investigators found that levels of HIV and HIV replication in both the bloodstream and lymph nodes were far higher in the 18 controls than in the 15 long-term non-progressors. The controls had at least five times as many cells containing HIV DNA than the long-term non- progressors and had levels of viral replication four- to 10-fold higher. Levels of cell-free virus were up to 20 times higher in the blood of the controls than in that of the long-term non-progressors.
Although HIV could not be isolated from the plasma of the long-term non-progressors, the researchers cultured the virus from immune system cells in these patients' lymph nodes, indicating that HIV is infectious and able to replicate in such people.
In addition, long-term non-progressors had higher levels of neutralizing antibodies than patients with progressive disease, and the blood of each of seven long-term non-progressors tested had the ability to kill HIV-infected cells.
"The presence of high titers of neutralizing antibodies, together with consistent detection of HIV-specific cytotoxic immune responses, indicates that both antibody and cell-mediated responses are preserved in long-term non-progressors," says Dr. Fauci. "This suggests that these individuals are constantly exposed to HIV antigens, yet somehow control the infection. Further study of these individuals may lead to insights into the mechanisms that prevent progression to advanced HIV disease."
Co-authors of Drs. Pantaleo and Fauci include Mauro Vaccarezza, M.D., Cecilia Graziosi, Ph.D., Oren J. Cohen, M.D., Stefano Menzo, M.D., and James F. Demarest, B.S., of the LIR; Lewis K. Schrager, M.D., of NIAID's Division of AIDS; Susan Buchbinder, M.D., of the San Francisco Department of Public Health; David Montefiori, Ph.D., of the Duke University Medical Center; Jan M. Orenstein, M.D., of the George Washington University; Cecil Fox, Ph.D., of Molecular Histology, Inc., Gaithersburg, Md.; Joseph B. Margolick, M.D., Ph.D., of the Johns Hopkins School of Public Health; and Janis V. Giorgi, Ph.D., of the UCLA School of Medicine.
NIAID, a component of the National Institutes of Health (NIH), supports investigators and scientific studies at universities, medical schools, hospitals and research institutions in the United States and abroad aimed at preventing, diagnosing and treating such illnesses as AIDS, tuberculosis and asthma as well as allergies. NIH is an agency of the U.S. Public Health Service, part of the U.S. Department of Health and Human Services.