VIROLOGICAL AND IMMUNOLOGICAL CHARACTERIZATION OF LONG-TERM SURVIVORSOF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 INFECTION

Background. In most subjects infected with human immunodeficiency viru s 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. Stud ies of these subjects, termed long-term survivors, may yield important clues for the development of prophylactic and therapeutic interventio ns against the acquired immunodeficiency syndrome. Methods and Results . We studied 10 seropositive subjects who remained asymptomatic with n ormal and stable CD4+ lymphocyte counts despite 12 to 15 years of HIV- 1 infection. Plasma cultures were uniformly negative for infectious vi rus. However, particle-associated HIV-1 RNA was detected in four subje cts with a sensitive branched-DNA signal-amplification assay, whereas in five others the levels of HIV-1 RNA were too low to detect. Infecti ous 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 c ulture. The other six subjects had no detectable infectious virus in t heir PBMC. A quantitative polymerase-chain-reaction assay revealed tha t all subjects had detectable but low titers of viral DNA in PBMC. Ove rall, the viral burden in the plasma and PBMC of long-term survivors w as orders of magnitude lower than that typically found in subjects wit h progressive disease. There was no in vitro evidence of resistance by host CD4+ lymphocytes to HIV-1 infection. However, longterm survivors had a vigorous, virus-inhibitory CD8+ lymphocyte response and a stron g neutralizing-antibody response. In two subjects the kinetics of vira l replication was consistent with the presence of a substantially atte nuated strain of HIV-1. Conclusions. Subjects 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.