Background: To determine the contribution of HIV-1 replication rate to steady-state plasma HIV-1 RNA concentration in subjects who are not receiving antiretroviral therapy.

Methods: 14 subjects enrolled in a study of the effects of antiretroviral therapy on HIV-1-specific immune responses in lymph nodes were evaluated.  2 subjects were excluded from further analysis because they had a genetic polymorphism known to affect HIV-1 pathogenesis (CCR5D32) or because they were infected with an HIV-1 phenotype associated with rapid viral replication and disease progression (syncytium induction in MT-2 cell culture).  For the remaining 12 subjects median plasma HIV-1 RNA was 29,255 copies/mL and median CD4+ lymphocyte count was 312 cells/mm³.  8 subjects were antiretroviral naïve and 3 subjects had been previously treated with zidovudine monotherapy (n = 2) or D4T and 3TC (n = 1).  All subjects had been off antiretroviral therapy for a minimum of 90 days prior to study entry.  First passage HIV-1 isolates were obtained from specimens collected at study entry by standard co-culture methods and viral stocks titered by end-point dilution on seronegative donor lymphoblasts.  Kinetics of p24 antigen production were measured after inoculation of lymphoblasts with first passage isolates.  All lymphoblasts used for virus isolation, titration, and replication rate analysis were obtained from a single donor.  Data collected during the exponential phase of culture p24 antigen accumulation between culture days 1 and 6 were analyzed by linear regression of semi-logarithmic plots of culture supernatant p24 concentration versus time to determine the ex vivo HIV-1 replication rate.

Results:  HIV-1 ex vivo replication rate ranged from 0.15 to 0.76 log₁₀ p24 day^-1.  There was a linear relationship between plasma HIV-1 RNA and HIV-1 replication rate (r² = 0.68, = p < 0.001) that extended over a 2.5 log₁₀ range of plasma HIV-1 RNA concentrations.

Conclusions:  Non-syncytium-inducing HIV-1 isolates from persons who are not treated with antiretroviral agents display a range of ex vivo replication rates.  A large portion of inter-person differences in plasma HIV-1 RNA can be explained by differences in HIV-1 ex vivo replication rate.  Our findings suggest that HIV-1 replication rate is an important determinant of HIV-1 disease progression.