Differences in disease progression in a cohort of long-term non-progressors after more than 16 years of HIV-1 infection Berta Rode ´s, Carlos Toro, Ellen Paxinos a , Eva Poveda, Manuel Martinez-Padial b , Jose ´ Miguel Benito, Victoria Jimenez, Terri Wrin b , Sylvina Bassani and Vincent Soriano Background: It is unclear whether resistance to immunologic damage in long-term non-progressors (LTNP) will last indefinitely or whether it merely represents the extreme of a Gaussian distribution, and therefore progression will occur eventually. Patients and methods: A cohort of 19 LTNP was established in 1997. Plasma viraemia and CD4 cell counts were measured two to three times each year until 2003. Analyses of nef and vpr viral genes, CCR5 genotypes, co-receptor tropism, viral replication capacity, and immunological parameters were performed. Results: Twelve subjects (non-progressors, NP) showed stable CD4 cell counts over the 6-year follow-up, while seven (slow progressors, SP) showed a trend towards progressive CD4 cell depletion; however, only three SP experienced significant CD4 cell count declines. All SP had detectable plasma HIV-RNA (median 1118 copies/ml). In contrast, five of 12 NP had always undetectable viraemia. Only one patient showed a deletion in nef. The vpr R77Q change was recognized in seven patients. All patients were infected with R5 viruses. The virus replicative capacity was reduced in all tested individuals (range 5–93%). None of the patients was homozygous for the delta-32 CCR5 genotype, which was found in heterozygosis in three. CD8 T-cell activation was low in all but three individuals, all of whom had detectable viraemia and showed progressive CD4 cell depletion. Cytotoxic T lymphocyte responses were similar to those found in a control group of HIV progressors. Conclusions: A substantial proportion of LTNP show low-level virus replication and progressive loss of CD4 T cells over time. Progressive immunologic damage seems to be directly associated with some degree of virus replication and T-cell activation. & 2004 Lippincott Williams & Wilkins AIDS 2004, 18:1109–1116 Keywords: long-term non-progressors, disease progression, natural history, viral fitness Introduction The course of HIV-1 infection varies greatly among infected patients. In a small proportion of individuals (1–5%), HIV-1 seems to be less pathogenic and there is no apparent progression. By definition, these long- term non-progressors (LTNP) remain asymptomatic, with CD4 cell counts . 500 3 10 6 cells/l and low or undetectable viral load, in the absence of any anti- retroviral therapy. The cause of the lack of progression in these persons is unclear, but it seems to result from the interaction between multiple factors linked to Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. From the Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain, a Virologic Inc, South San Francisco, California, USA, and the b Microbiology Department, Hospital Carlos III, Madrid, Spain. Correspondence to V. Soriano, Calle Nueva Zelanda 54, 4B, Madrid 28035, Spain. Received: 17 December 2003; revised: 22 February 2004; accepted: 16 March 2004. DOI: 10.1097/01.aids.0000125962.16506.f9 ISSN 0269-9370 & 2004 Lippincott Williams & Wilkins 1109