Replication Capacity of Viruses from Acute Infection Drives HIV-1 Disease Progression.
The viral genotype has been shown to play an important role in HIV pathogenesis following transmission. However, the viral phenotypic properties that contribute to disease progression remain unclear. Most studies have been limited to the evaluation of Gag function in the context of a recombinant virus backbone. Using this approach, important biological information may be lost, making the evaluation of viruses obtained during acute infection, representing the transmitted virus, a more biologically relevant model. Here, we evaluate the roles of viral infectivity and the replication capacity of viruses from acute infection in disease progression in women who seroconverted in the CAPRISA 004 tenofovir microbicide trial. We show that viral replication capacity, but not viral infectivity, correlates with the set point viral load (Spearmanr= 0.346;P= 0.045) and that replication capacity (hazard ratio [HR] = 4.52;P= 0.01) can predict CD4 decline independently of the viral load (HR = 2.9;P= 0.004) or protective HLA alleles (HR = 0.61;P= 0.36). We further demonstrate that Gag-Pro is not the main driver of this association, suggesting that additional properties of the transmitted virus play a role in disease progression. Finally, we find that although viruses from the tenofovir arm were 2-fold less infectious, they replicated at rates similar to those of viruses from the placebo arm. This indicates that the use of tenofovir gel did not select for viral variants with higher replication capacity. Overall, this study supports a strong influence of the replication capacity in acute infection on disease progression, potentially driven by interaction of multiple genes rather than a dominant role of the major structural genegagIMPORTANCEHIV disease progression is known to differ between individuals, and defining which fraction of this variation can be attributed to the virus is important both clinically and epidemiologically. In this study, we show that the replication capacity of viruses isolated during acute infection predicts subsequent disease progression and drives CD4 decline independently of the viral load. This provides further support for the hypothesis that the replication capacity of the transmitted virus determines the initial damage to the immune system, setting the pace for later disease progression. However, we did not find evidence that the major structural genegagdrives this correlation, highlighting the importance of other genes in determining disease progression.
Institute of Infectious Diseases and Molecular Medicine, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Philippe
P
Selhorst
Institute of Infectious Diseases and Molecular Medicine, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Carina
C
Combrinck
Institute of Infectious Diseases and Molecular Medicine, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Nonkululeko
N
Ndabambi
Institute of Infectious Diseases and Molecular Medicine, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Sherazaan D
SD
Ismail
Institute of Infectious Diseases and Molecular Medicine, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Melissa-Rose
MR
Abrahams
Department of Statistical Sciences, Faculty of Science, University of Cape Town, Cape Town, South Africa.
Miguel
M
Lacerda
Centre for the AIDS Programme of Research in South Africa, University of KwaZulu-Natal, Durban, South Africa.
Natasha
N
Samsunder
Centre for the AIDS Programme of Research in South Africa, University of KwaZulu-Natal, Durban, South Africa.
Nigel
N
Garrett
Centre for the AIDS Programme of Research in South Africa, University of KwaZulu-Natal, Durban, South Africa.|Department of Epidemiology, Columbia University, New York, New York, USA.
Quarraisha
Q
Abdool Karim
Centre for the AIDS Programme of Research in South Africa, University of KwaZulu-Natal, Durban, South Africa.|Department of Epidemiology, Columbia University, New York, New York, USA.
Salim S
SS
Abdool Karim
Institute of Infectious Diseases and Molecular Medicine, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa carolyn.williamson@uct.ac.za.|Centre for the AIDS Programme of Research in South Africa, University of KwaZulu-Natal, Durban, South Africa.|National Health Laboratory Service, Johannesburg, South Africa.
Carolyn
C
Williamson
D000890:Anti-Infective Agents / Q000008:administration & dosage; D018450:Disease Progression; D018562:Disease Transmission, Infectious / Q000517:prevention & control; D005260:Female; D015658:HIV Infections / Q000473:pathology* / Q000517:prevention & control / Q000821:virology*; D015497:HIV-1 / Q000302:isolation & purification / Q000502:physiology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D010919:Placebos / Q000008:administration & dosage; D016032:Randomized Controlled Trials as Topic; D014779:Virus Replication
D000890:Anti-Infective Agents; D010919:Placebos
CAPRISA 004; HIV; acute infection; disease progression; heterosexual transmission; infectivity; isolates; pathogenesis; replication capacity; tenofovir