Background: A cohort of 19 long-term non-progressors (LTNP) was established in 1997. At that time, all had HIV infection proven for at least 10 yrs without antiretroviral therapy, CD4 counts > 500 cells/mm³, and lacked HIV-related symptoms. One of them was known to have stored sera already positive for HIV antibodies since 1979. At this time, it is unclear whether resistance to immunologic damage in these patients will persist forever or if they merely represents the extreme of a normal distribution, and therefore progression will be just a matter of time in them. Herein, we describe their main features of this cohort and their its evolution over the last 6 yrs.

Methods: Plasma viral load (pVL) and CD4 counts were measured 2–3 times each year between 1997–2002. In recent samples, we also characterized the viruses for gag/pol subtypes, Nef deletions, co-receptor tropism, and replication capacity. They were also assayed for CCR5 genotypes and T-cell activation (measuredmeasured as the expression of CD38 on CD8⁺ cells)were all examined in recent specimens.

Results: Of the 19 patients (pts), 13 were male and 14 were former iv drug users. Eleven (11) subjects had stable CD4 counts. Four (4) subjects showed a trend for progressive CD4 depletion, but only one of them had significant CD4 declines have (average loss of 144 cells/year). All these 4 subjects showing declining CD4s had had detectable viremia at more than one time point (average pVL = 1,500 c/mlml on average, but occasionally rising up to pVL = 15,000 c/ml). In contrast, 10 10 of the 11 subjects with stable CD4 counts, had who have kept pVL < 50 c/ml at all time points.  have remained with stable CD4 counts over time.

All viruses from individuals in this cohort belonged to subtype B, and none possessed deletions at the Nef gene. Ten (10) of 11 pts were infected with R5-using monotropic viruses. One pt showed a shift from exclusive R5-using virus population to a mixed X4/R5-using virus population. This switch was coincident with a mean loss of 80 CD4⁺ cells/year over the last 2 yrs. The virusViral replication  replicative capacity was tested measured in 6 individuals, and all showed severe replication impairments, ranging from 3% to 45% in respect to a reference strainranging from 5%–120% relative to wild-type. Those with stable CD4 counts had the lowest RC. In cross-neutralization assays, plasma from latest time points neutralized virus from previous time points. No pt was homozygous for the delta-32 CCR5 genotype, which was found in heterozygosis in only 3 subjects. Finally, most CD4 and CD8 cells from these pts expressed a naive phenotype. CD8 activation was low in all but 3 individuals, all of whom had detectable pVL.

Conclusion: The majority of LTNP remain with low or undetectable pVL and high and stable CD4 counts over time. Most of them carry viruses exhibiting a low replicative capacity and CCR5 tropism. Progressive immunologic damage seems directly associated with some degree of HIV replication and T-cell activation.