Jeffrey T. Safrit

Virologic and Immunologic Characterization of Long-Term Survivors of Human Immunodeficiency Virus Type 1 Infection

BACKGROUNDnIn most subjects infected with human immunodeficiency virus type 1 (HIV-1), clinical or laboratory evidence of immunodeficiency develops within 10 years of seroconversion, but a few infected people remain healthy and immunologically normal for more than a decade. Studies of these subjects, termed long-term survivors, may yield important clues for the development of prophylactic and therapeutic interventions against the acquired immunodeficiency syndrome.nnnMETHODS AND RESULTSnWe studied 10 seropositive subjects who remained asymptomatic with normal and stable CD4+ lymphocyte counts despite 12 to 15 years of HIV-1 infection. Plasma cultures were uniformly negative for infectious virus. However, particle-associated HIV-1 RNA was detected in four subjects with a sensitive branched-DNA signal-amplification assay, whereas in five others the levels of HIV-1 RNA were too low to detect. Infectious HIV-1 was detected in peripheral-blood mononuclear cells (PBMC) of three subjects by standard limiting-dilution cultures, and infectious virus was recovered from another subject with use of a CD8-depleted culture. The other six subjects had no detectable infectious virus in their PBMC. A quantitative polymerase-chain-reaction assay revealed that all subjects had detectable but low titers of viral DNA in PBMC. Overall, the viral burden in the plasma and PBMC of long-term survivors was orders of magnitude lower than that typically found in subjects with progressive disease. There was no in vitro evidence of resistance by host CD4+ lymphocytes to HIV-1 infection. However, long-term survivors had a vigorous, virus-inhibitory CD8+ lymphocyte response and a strong neutralizing-antibody response. In two subjects the kinetics of viral replication were consistent with the presence of a substantially attenuated strain of HIV-1.nnnCONCLUSIONSnSubjects who remain asymptomatic for many years despite HIV-1 infection have low levels of HIV-1 and a combination of strong virus-specific immune responses with some degree of attenuation of the virus.

Adaptive Evolution of Human Immunodeficiency Virus-Type 1 During the Natural Course of Infection

The rate of progression to disease varies considerably among individuals infected with human immunodeficiency virus-type 1 (HIV-1). Analyses of semiannual blood samples obtained from six infected men showed that a rapid rate of CD4 T cell loss was associated with relative evolutionary stasis of the HIV-1 quasispecies virus population. More moderate rates of CD4 T cell loss correlated with genetic evolution within three of four subjects. Consistent with selection by the immune constraints of these subjects, amino acid changes were apparent within the appropriate epitopes of human leukocyte antigen class I-restricted cytotoxic T lymphocytes. Thus, the evolutionary dynamics exhibited by the HIV-1 quasispecies virus populations under natural selection are compatible with adaptive evolution.

hu-PBL-SCID mice can be protected from HIV-1 infection by passive transfer of monoclonal antibody to the principal neutralizing determinant of envelope gp120

OBJECTIVEnTo determine whether passive transfer of a monoclonal antibody specific for the principal neutralizing determinant in the V3 region of HIV-1IIIB gp120 can protect mice with severe combined immunodeficiency (SCID) transplanted with normal human peripheral blood leukocytes (hu-PBL), designated hu-PBL-SCID mice, from subsequent challenge with the homologous viral strain.nnnDESIGN AND METHODSnhu-PBL-SCID mice were given intraperitoneal injections of an anti-HIV-1 neutralizing murine monoclonal antibody (BAT123), its mouse-human chimeric form (CGP 47 439), or a control murine antibody (PNTU), at a dose of 40 mg/kg. The mice were then challenged intraperitoneally with 10 mouse infectious doses of HIV-1IIIB. Three weeks later the mice were killed, and spleen cells and peritoneal lavage collected for determination of infection by coculture for viral isolation and by detection of HIV-1 DNA using polymerase chain reaction (PCR).nnnRESULTSnAll three antibodies had similar serum half-lives of 9-12 days. No toxicity was observed in the animals. HIV-1 was recovered by coculture from five out of the six mice given PNTU, and by PCR from two out of the six mice given PNTU, but was not recovered by either technique from any of the 12 mice given BAT123 or CGP 47 439.nnnCONCLUSIONnBAT123 and CGP 47 439, which are specific for the principal neutralizing determinant of HIV-1IIIB, protect hu-PBL-SCID mice from infection by this viral strain. Our findings support the use of the hu-PBL-SCID mouse as an in vivo model for studying protection against HIV-1 infection by passive immunization with anti-HIV-1 neutralizing antibodies.

The maturing immune system: implications for development and testing HIV-1 vaccines for children and adolescents

Inclusion of children and adolescents in clinical trial research and particularly HIV vaccine trials is difficult. Ethico-legal issues concerning age of informed consent protection of children and reporting of illegal sexual activity and sexually transmitted diseases confront researchers. Socio-behavioral issues include assessment of true understanding of the consent form and possible disinhibition of sexual behaviour whilst participating in trials. There is also a lack of experience in recruiting and retaining adolescents and the provision of youth-friendly services. These are thought to be an important prerequisite for adolescent trials and are non-existent in many HIV trial sites. Yet these problems can and must be addressed. There are physiological and immunological differences between children and adults that may change the safety and efficacy of developed vaccines. The purpose of this review is primarily to highlight the immunological differences between infants adolescents and adults and to describe some of the reported disparities between these age groups in their responses to licensed as well as other experimental vaccines. (excerpt)

Cd8+ T-cell-mediated suppression of Hiv replication in the first year of life: association with lower viral load and favorable early survival

Objective and design:To study the role and development of non-cytotoxic CD8+ T-cell-mediated suppression of HIV replication in early perinatal HIV infection in a prospective study of vertically infected infants. CD8 T-cell-mediated HIV suppression was measured several times during the first year of life and correlated with viral load, cytotoxic T-cell (CTL) activity, in vitro antibody production (IVAP) and clinical outcome. Methods:CD8+ T-cell-mediated HIV suppression was measured by comparing the amount of p24 antigen produced by endogenously infected lymphocytes with cultures of the same number of autologous CD4+ T cells from which CD8+ cells were removed immunomagnetically. CD8 viral suppressive activity (VSA) was defined as a ≥50% reduction in p24 antigen in the cultures containing CD8+ cells. Results:CD8+ T-cell-mediated HIV VSA was detected in 11/16 infants in the first year of life, including six/nine infants studied before 6 months and as early as 3 weeks of age. Infants who demonstrated CD8 VSA had a lower early peak and 6-month ‘setpoint’ plasma HIV RNA concentration than infants who lacked CD8 VSA [1.51 versus 4.94 and 0.094 versus 0.639 × 106 copies/ml, respectively, and higher CD4 percentage at 1 year of age. Survival of infants lacking CD8 VSA (four/six were rapid progressors) was shorter than for infants who demonstrated CD8 VSA (none out of 10 were rapid progressors). CD8 VSA was present before CTL and before or at the same time as IVAP in two of two and 11 of 14 infants studied, respectively. Conclusions:CD8+ T-cell-mediated VSA can be demonstrated in a large proportion of HIV-infected infants early in the course of infection. This non-cytolytic HIV-suppressive immune response appears to play an important protective role in the early control of perinatal HIV infection at a time when other immune responses are either absent or deficient.

Response: HIV-1 Evolution and Disease Progression

REFERENCES AND NOTES se that destroys the host. Thus, within a particular host, diversity is driven by the collective sum of all the selective forces acting on the HIV-1 quasispecies virus population, rather than a specific immune parameter by or in itself (4). The theory predicts two possible outcomes. First, infected individuals with diversity higher than their individual specific threshold lose immune control and rapidly progress to AIDS, while those below their individual specific threshold remain clinically stable. Second, an increase in antigenic diversity over time in the same individual gives rise to loss of immune control and faster progression to AIDS once the individuals specific threshold is crossed. The fact that the magnitude of the diversity threshold could be different in different infected individuals is a result of the inherent plasticity of the mathematical model used to derive the antigenic diversity threshold theory (1, 2). As a consequence, the model becomes virtually untestable. The actual model could encompass many different possible parameters that can trigger the trajectory to AIDS, all of which are sensitive to initial conditions (5) and better expressed as a nondimensional threshold condition (6). Thus, stochastic simulations of the infection process only partially characterize the model dynamics (5). The results of our study (7) do not support a model that relates increasing antigenic diversity to pathogenic progres-