HIV This Week

Keele BF, Tazi L, Gartner S, Liu Y, Burgon TB, Estes JD, Thacker TC, Crandall KA, McArthur JC, Burton GF. Characterization of the Follicular Dendritic Cell Reservoir of HIV-1. J Virol. 2008 Apr 2 [Epub ahead of print]

Throughout the natural course of HIV infection, follicular dendritic cells trap and retain large quantities of particle-associated HIV RNA in the follicles of secondary lymphoid tissue. Keele and colleagues previously found that murine follicular dendritic cells in vivo could maintain trapped virus particles in an infectious state for at least 9 months. Here they sought to determine if human follicular dendritic cells serve as an HIV reservoir, based on the criteria that virus therein must be replication competent, genetically diverse and archival in nature. They tested their hypothesis using post-mortem cells and tissues obtained from three, HIV-infected subjects and ante-mortem blood samples obtained from one of them. Replication competence was determined using co-culture, while genetic diversity and the archival nature of virus were established using phylogenetic and population genetics methods. The authors found that follicular dendritic cell -trapped virus was replication-competent and demonstrated greater genetic diversity than that found in most other tissues and cells. Antiretroviral resistant variants were also detected on follicular dendritic cells that were not present elsewhere. Furthermore, genetic similarity was observed between follicular dendritic cell-trapped HIV and viral species recovered from peripheral blood mononuclear cells obtained 21 and 22 months ante-mortem, but not present in samples obtained 4 and 18 months prior to death, indicating that follicular dendritic cells can archive HIV. These data indicate that follicular dendritic cells represent a significant reservoir of infectious and diverse HIV thereby providing a mechanism for viral persistence for months to years.

Editor’s Note: It is believed that stable viral reservoirs established before the initiation of antiviral therapy are responsible for the low level residual viraemia that can be detected with ultrasensitive assays in virtually all people living with HIV with “undetectable” viral loads on standard assays. The genetic diversity of HIV found in follicular dendritic cells in this small post-mortem study suggests that these cells may be t rapping HIV throughout the course of the disease, however it is unclear whether this would be specific to individuals with worsening clinical progress and more frequent during failures.

Hendrickson SL, Jacobson LP, Nelson GW, Phair JP, Lautenberger J, Johnson RC, Kingsley L, Margolick JB, Detels R, Goedert JJ, O’Brien SJ. Host Genetic Influences on Highly Active Antiretroviral Therapy Efficacy and AIDS-Free Survival. J Acquir Immune Defic Syndr. 2008;48(3):263-71.

Hendrickson and colleagues studied the influence of AIDS-restriction genes (ARGs) CCR5-Delta32, CCR2-64I, SDF1- 3’ A, IL10- 5’ A, CX3CR1V249I, CX3CR1-T280M, and MDR1-C3435T and haplotypes of the CCR5 P1 promoter and RANTES variants -403A, In1.1C, 3’ 222C, and -28G among HIV-negative infected patients on highly active antiretroviral therapy in the Multicenter AIDS Cohort Study (MACS) and the Multicenter Hemophilia Cohort Study (MHCS). Their results indicate that several AIDS-restriction genes also influence therapy efficacy (ie, the success in viral suppression) and subsequent progression to AIDS while on highly active antiretroviral therapy. CCR5-Delta32 decreased time to viral suppression (<200 HIV RNA copies/mL, relative hazard [RH] = 1.40; P = 0.008) and was protective against AIDS (RH = 0.11; P = <0.0001), whereas the CCR5 P1 haplotype was associated with delayed viral suppression (RNA <50 copies/mL, odds ratio [OR] = 0.65; P = 0.03) and accelerated time to AIDS (RH = 2.68; P = 0.02). SDF1-3’ A reduced viral suppression (OR = 0.61; P = 0.02) and accelerated AIDS (RH = 3.18; P = 0.009). Accelerated AIDS progression was also observed with the RANTES haplotype carrying RANTES-IN1.1C and RANTES- 3’ 222C (P = 0.005 to 0.007). In contrast, the RANTES haplotype H1, which lacks suspected deleterious single-nucleotide polymorphisms, was protective against AIDS. CX3CR1-V249I seemed to accelerate viral suppression (RNA <50 copies/mL, OR = 1.27; P = 0.01). AIDS-restriction gene influence after highly active antiretroviral therapy suggests residual HIV-1 replication, and spread continues even in patients successfully suppressing detectable viral RNA.

Editor’s Note: Host genetics likely plan an important role in treatment success. AIDS restriction genes are genes with polymorphisms that influence HIV infection and AIDS progression in untreated patients, either positively or negatively. These are early days but it appears that genes involved with the CCR5 viral pathway are particularly important to treatment success.

Readinger JA, Schiralli GM, Jiang JK, Thomas CJ, August A, Henderson AJ, Schwartzberg PL. Selective targeting of ITK blocks multiple steps of HIV replication. Proc Natl Acad Sci U S A . 2008;105(18):6684-9.

Treatment for HIV has relied on the use of antiretroviral agents that can be subject to the development of resistant viruses. The study of inhibitors directed against cellular proteins required for HIV replication is therefore of growing interest. Inducible T cell kinase (ITK) is a Tec family tyrosine kinase that regulates T cell receptor (TCR)-induced activation of PLCgamma-1, Ca(2+) mobilization and transcription factor activation, and actin rearrangement downstream of both TCR and chemokine receptors. Because productive infection of T cells with HIV requires T cell activation, chemokine receptors and actin reorganization, Readinger and colleagues asked whether ITK affects HIV infection using ITK-specific siRNA, a kinase-inactive ITK mutant or an ITK inhibitor. They demonstrate that loss of ITK function resulted in marked reductions in intracellular p24 levels upon HIV infection. Loss of ITK function after establishment of HIV infection also decreased virus spread within the culture. Inhibition of ITK did not affect expression of the HIV coreceptors CD4 or CXCR4 but partially blocked HIV viral entry, an effect that correlated with decreased actin polarization to gp120. Additionally, ITK was required for efficient HIV transcription, and over-expression of ITK increased both viral transcription and virus-like particle formation. The data suggest that inhibition of ITK blocks HIV infection by affecting multiple steps of HIV replication.

Editor’s Note: Inducible T cell kinase is a cellular protein that appears to regulate HIV replication, including viral entry, transcription, virion assembly and release. Because it affects multiple stages of the HIV replication life cycle, an inducible T cell kinase inhibitor could be an important addition to antiretroviral drug regimes.