Variations in Response to HIV Exposure and Infection: Long- Term Survivors and Others
Do some HIV-infected individuals have a particular, protective quirk in their immune systems that allows them to remain healthy for 10 years or more?
NIAID-supported scientists and other researchers gathered in February 1993 to share preliminary findings about so-called long-term survivors from their studies of the natural course of HIV infection. The conference also addressed the possible biological and genetic mechanisms that might explain resistance to HIV infection and disease. Participants included epidemiologists, clinicians, and laboratory scientists.
NIAID is intensively studying many of the factors that might explain why a number of individuals continue to remain healthy, despite being infected with HIV. This research should provide insights as to how to control HIV infection in others whose progression to active HIV disease unfortunately is more rapid. Understanding the variations in response to HIV exposure and infection is critical to designing new approaches for therapy and vaccines.
The presenters focused on three unusual, poorly understood and potentially important ways that patients react to HIV:
- maintaining stable levels of certain crucial immune system cells, the CD4+ T cells that HIV normally kills, for seven to 10 years or more following HIV infection.
- losing a significant proportion of CD4+ T cells to HIV but apparently remaining healthy for an unusually long time.
- not developing any apparent evidence of infection despite multiple exposures to HIV.
The scientists developed the three categories base on observations from the Multicenter AIDS Cohort Study (MACS) and the San Francisco Men's Health Study (SFMHS). Additional data come from other HIV/AIDS natural history studies, including the San Francisco City Clinic cohort study of gay men that the Centers for Disease Control and Prevention supports, the Edinburgh cohort study of hemophiliacs, a study of female sex workers in Nairobi, Kenya, and several other studies of women, children, injection-drug users, blood transfusion recipients and hemophiliacs.
Begun in 1983 by NIAID, MACS and SFMHS have enrolled more than 6,000 gay and bisexual men to determine risk factors that might influence the course of HIV infection and disease. MACS sites are at The Johns Hopkins University in Baltimore, Northwestern University in Chicago, the University of California at Los Angeles and the University of Pittsburgh. The data analysis center for MACS is located at Johns Hopkins. SFMHS is located at the University of California at Berkeley.
HIV infection without loss of CD4+ T cells
MACS investigators have found more than 60 men infected with HIV for seven to eight years who have maintained stable levels of CD4+ T cells. The normal range of CD4+ T cell counts in uninfected adults is 800 to 1,200 per cubic millimeter of blood (mm3).
To understand more about the mens' apparently healthy status, MACS researchers are comparing these men to two other groups of MACS participants, those who manifested an unusually rapid CD4+ T cell decline after infection, and those displaying a CD4+ T cell decline considered average for HIV- infected people. Immunologists and virologists are collaborating on the study to compare the nature of the men's immune responses and the characteristics of the particular strain of HIV with which they are infected to see if important differences exist.
Investigators from the San Francisco City Clinic are engaged in similar research among 40 men whose CD4+ T cell counts have remained above 500 cells/mm3 for 10 to 15 years following development of antibodies to HIV.
HIV infection and loss of CD4+ T cells, without disease progression
Investigators studying HIV-infected gay men, women, pediatric patients and hemophiliacs presented data on a small number of individuals whose CD4+ T cell counts have dropped below 200 cells/mm3, but have remained relatively healthy and survived for unusually long periods of time.
Usually, people with counts below 200 cells/mm3 are at increased risk of developing AIDS-related opportunistic infections, such as Pneumocystis carinii pneumonia and AIDS- related cancers. When AIDS patients die, they usually have a CD4+ T cell count of less than 50 cells/mm3.
Laboratory scientists investigating this aspect of HIV infection stressed that their understanding of this phenomenon is rudimentary and that further immunologic and virologic studies will be required before a biological explanation can be found.
Exposure to HIV without infection
In an ongoing study in Nairobi, Kenya, Dr. Neil Simonsen from the University of Manitoba in Winnipeg, Canada, has found evidence of female sex workers exposed to HIV who do not develop any detectable infection or disease.
Almost 10 percent of the approximately 260 women in this group have not developed antibodies to HIV, remaining seronegative for three years despite ongoing unprotected sexual exposure to HIV-infected men. These apparently uninfected women are being intensively studied for possible evidence of intrinsic resistance to HIV. In addition, MACS investigators reported on gay men who remain uninfected despite repeated high-risk exposure to HIV, while other scientists discussed hemophiliacs and blood-transfusion recipients who have remained uninfected even though they have received contaminated blood products. Other researchers presented findings from studies of children who are not infected despite being born to HIV-infected mothers.
Three factors involved
At the meeting, scientists suggested that at least three factors might be responsible for the unusual outcomes: intrinsic genetic resistance to HIV, variations in the immune response among different individuals and differences in the fundamental characteristics of the particular strains of HIV.
NIAID has begun collaborative work to explore these and other factors. The investigators include epidemiologists, clinicians, molecular biologists, virologists and immunologists. The team will use clinical specimens from the natural history studies.
Genetic resistance to HIV
Specific genes might be responsible for resistance to HIV and long-term survival, according to Dr. Miles Cloyd from the University of Texas Medical Branch, Galveston, who presented his work at the meeting.
In the most extensive such studies to date, using HIV infection of human CD4+ T cells in culture, Dr. Cloyd has found evidence for the existence of a normal human gene, present only in certain people, that causes their cells to become resistant to infection with certain HIV strains. The gene appears to be similar to a known resistance gene in mice, Fv-1. Studies of how the gene can make cells resistant to HIV infection are in progress.
In addition, a survey of studies of retroviruses other than HIV indicates animals have many resistance genes capable of completely preventing virus-induced diseases such as leukemia. Scientists know how these animal genes cause resistance, and they may represent possible models for resistance to HIV. In particular, many of the well-studied resistance genes in mice seem to be related to virus envelope genes. This genetic similarity may make animals resistant to disease by a process related to the phenomenon of viral interference, where infection of a cell by one virus renders a cell resistant to infection by a related second virus. Viral interference has been studied only to a limited degree with HIV and may represent a fruitful area for future studies on resistance.
Inducing resistance via gene therapy also is a possibility. Investigators have identified an increasing number of cellular genes whose products are required for the efficient replication of HIV. These genes represent potential ways to cause opposition to HIV, if appropriate inhibitors or resistant variants can be found and introduce into cells using gene therapy techniques.
Variations in response
A number of researchers reported that the groups of proteins called human leukocyte antigens (HLA) may be associated with altered reactions to HIV infection. These antigens are found on the surfaces of certain human cells and play an integral role in immune system responses.
HLA makeup is determined by an individual's specific group of HLA genes and is known to vary from person to person. The scientists suggested that an individual's genetic constitution--and therefore HLA type--may determine the way the immune system responds to HIV, significantly influencing the course of disease.
Dr. George Shaw, University of Alabama at Birmingham, reported on the use of a new technique, quantitative competitive PCR. The test is capable of detecting HIV particles in the plasma of patients who, by conventional, culture-based tests, lack detectable virus.
The viral particles in these patients largely are defective and otherwise incapable of replication on their own, but could dramatically alter the course of HIV infection by interacting with cells of the immune system. Dr. Shaw, in collaboration with Dr. Jeffrey Lifson of Genelabs, currently is extending his studies in this area.