Central nervous system (CNS) HIV infection is a nearly universal facet of systemic infection. Although anti-retroviral therapy is generally effective in suppressing this infection and reducing its severe complications, reports of continued neurological abnormalities have questioned whether treatment developed for systemic efficacy is optimized for CNS infection. Shikuma et al. report that a ‘monocyte efficacy’ score based on cell culture studies and applied to antiretroviral drugs correlated with neuropsychological performance in a previously reported cohort. Although there are important questions regarding the theoretical underpinnings of both this score and its application, the findings present a novel slant on therapy.
References
1.
EllisR.J., HsiaK., SpectorS.A.Cerebrospinal fluid human immunodeficiency virus type 1 RNA levels are elevated in neurocognitively impaired individuals with acquired immunodeficiency syndrome. Ann Neurol1997; 42: 679–688.
2.
SpudichS., LolloN., LieglerT., DeeksS.G., PriceR.W.Treatment benefit on cerebrospinal fluid HIV-1 levels in the setting of systemic virological suppression and failure. J Infect Dis2006; 194: 1686–1696.
3.
SpudichS., GisslenM., HagbergL.Central nervous system immune activation characterizes primary human immunodeficiency virus 1 infection even in participants with minimal cerebrospinal fluid viral burden. J Infect Dis2011; 204: 753–760.
4.
CrewsL., PatrickC., AchimC.L., EverallI.P., MasliahE.Molecular pathology of neuro-AIDS (CNS-HIV). Int J Mol Sci2009; 10: 1045–1063.
5.
NaviaB.A., ChoE.S., PetitoC.K., PriceR.W.The AIDS dementia complex: II. Neuropathology. Ann Neurol1986; 19: 525–535.
6.
BhaskaranK., MussiniC., AntinoriA.Changes in the incidence and predictors of human immunodeficiency virus-associated dementia in the era of highly active antiretroviral therapy. Ann Neurol2008; 63: 213–221.
7.
LescureF.X., OmlandL.H., EngsigF.N.Incidence and impact on mortality of severe neurocognitive disorders in persons with and without HIV infection: a Danish nationwide cohort study. Clin Infect Dis2011; 15: 235–243.
8.
HeatonR.K., CliffordD.B., FranklinD.R.Jr.. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology2010; 75: 2087–2096.
9.
DeeksS.G.HIV infection, inflammation, immunosenescence, and aging. Annu Rev Med2011; 62: 141–155.
10.
YilmazA., PriceR.W., GisslenM.Antiretroviral drug treatment of CNS HIV-1 infection. J Antimicrob Chemother2012; 67: 299–311.
11.
CanestriA., LescureF.X., JaureguiberryS.Discordance between cerebral spinal fluid and plasma HIV replication in patients with neurological symptoms who are receiving suppressive antiretroviral therapy. Clin Infect Dis2010; 50: 773–778.
12.
EdénA., FuchsD., HagbergL.HIV-1 viral escape in cerebrospinal fluid of subjects on suppressive antiretroviral treatment. J Infect Dis2010; 202: 1819–1825.
13.
QueenS.E., MearsB.M., KellyK.M.Replication-competent simian immunodeficiency virus (SIV) Gag escape mutations archived in latent reservoirs during antiretroviral treatment of SIV-infected macaques. J Virol2011; 85: 9167–9175.
14.
LafeuilladeA.Eliminating the HIV reservoir. Curr HIV/ AIDS Rep2012; 9: 121–131.
15.
RobertsonK.R., SuZ., MargolisD.M.Neurocognitive effects of treatment interruption in stable HIV-positive patients in an observational cohort. Neurology2010; 74: 1260–1266.
16.
LetendreS., Marquie-BeckJ., CapparelliE.Validation of the CNS penetration-effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol2008; 65: 65–70.
17.
SmurzynskiM., WuK., LetendreS.Effects of central nervous system antiretroviral penetration on cognitive functioning in the ALLRT cohort. AIDS2011; 25: 357–365.
18.
MarraC.M., ZhaoY., CliffordD.B.Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance. AIDS2009; 23: 1359–1366.
19.
EllisR.J., BadieeJ., VaidaF.CD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy. AIDS2011; 25: 1747–1751.
20.
HeatonR.K., FranklinD.R., EllisR.J.HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol2011; 17: 3–16.
21.
CysiqueL.A., WatersE.K., BrewB.J.Central nervous system antiretroviral efficacy in HIV infection: a qualitative and quantitative review and implications for future research. BMC Neurol2011; 11: 148.
22.
SchnellG., PriceR.W., SwanstromR., SpudichS.Compartmentalization and clonal amplification of HIV-1 variants in the cerebrospinal fluid during primary infection. J Virol2010; 84: 2395–2407.
23.
LyonsJ., VennaN., ChoT.A.Atypical nervous system manifestations of HIV. Semin Neurol2011; 31: 254–265.
24.
GisslénM., PriceR.W., NilssonS.The definition of HIV-associated neurocognitive disorders: are we overestimating the real prevalence?BMC Infect Dis2011; 11: 356.
25.
ShikumaC.M., NakamotoB., ShiramizuB.Antiretroviral monocyte efficacy score linked to cognitive impairment in HIV. Antivir Ther2012; doi: 10.3851/IMP2411.
26.
GavegnanoC., SchinaziR.F.Antiretroviral therapy in macrophages: implication for HIV eradication. Antivir Chem Chemother2009; 20: 63–78.
27.
ValcourV.G., ShiramizuB.T., SithinamsuwanP.HIV DNA and cognition in a Thai longitudinal HAART initiation cohort: the SEARCH 001 Cohort Study. Neurology2009; 72: 992–998.
28.
LeeB., SharronM., MontanerL.J., WeissmanD., DomsR.W.Quantification of CD4, CCR5, and CXCR4 levels on lymphocyte subsets, dendritic cells, and differentially conditioned monocyte-derived macrophages. Proc Natl Acad Sci U S A1999; 96: 5215–5220.
29.
SonzaS., MaerzA., UrenS.Susceptibility of human monocytes to HIV type 1 infection in vitro is not dependent on their level of CD4 expression. AIDS Res Hum Retroviruses1995; 11: 769–776.
30.
NaifH.M., LiS., AlaliM.CCR5 expression correlates with susceptibility of maturing monocytes to human immunodeficiency virus type 1 infection. J Virol1998; 72: 830–836.
31.
ArrildtK.T., JosephS.B., SwanstromR.The HIV-1 env protein: a coat of many colors. Curr HIV/AIDS Rep2012; 9: 52–63.
32.
JosefssonL., KingM.S., MakitaloB.Majority of CD4+ T cells from peripheral blood of HIV-1-infected individuals contain only one HIV DNA molecule. Proc Natl Acad Sci U S A2011; 108: 11199–11204.
33.
SpivakA.M., SalgadoM., RabiS.A., O'ConnellK.A., BlanksonJ.N.Circulating monocytes are not a major reservoir of HIV-1 in elite suppressors. J Virol2011; 85: 10399–10403.
34.
SchnellG., JosephS., SpudichS., PriceR.W., SwanstromR.HIV-1 replication in the central nervous system occurs in two distinct cell types. PLoS Pathog2011; 7: e1002286.
