Inflammation in Chronic HIV Infection: What Can We Do?

Effectiveantiretroviraltherapy(ART)hasdramaticallyimprovedthelifeexpectancyofpersonslivingwithhumanimmunode-ﬁciency virus (HIV). However, even withlong-term, effective ART, HIV-infectedpersons have persistent, low-grade in-ﬂammation and immune activation [1]that are stronglyassociated with a height-ened risk for cardiovascular disease [2–4], osteoporosis [5], anemia [6], physicalfunction impairments and frailty [7],among other non-AIDS–deﬁning eventsand mortality [8,9].Forexample, a recentanalysis in the Multicenter AIDS CohortStudy found that levels of soluble CD14(sCD14),amarkerofmonocyteactivation,were signiﬁcantly higher in HIV-infectedmen, compared with HIV-uninfectedmen, but that they did not differ betweenHIV-infected men with and those with-out effective ART and changed very littleintheyearsfollowingARTinitiation[10].Given the long-term consequences ofchronic inﬂammation, there is an urgentneed to better understand the causesand develop interventions that attenuatethe effects of inﬂammation and immuneactivation in people living with HIV in-fection. The study by Hileman et al inthis issue of The Journal of Infectious Dis-eases offers insight into how the choice ofthe initial antiretroviral regimen affectssubsequent changes in inﬂammationand immune activation markers.Multiplefactorslikelycontributetothechronic inﬂammation and immune acti-vation found in HIV-infected personsduring ART, but the independent roleof each factor is difﬁcult to discern.HIV-infected persons with residual HIVtype 1 (HIV-1) replication, immune de-pletion, or hepatitis B or C virus coinfec-tion, especially those with underlyingﬁbrosis, exhibit higher levels of inﬂam-mation and immune activation [11, 12].Other chronic viral coinfections are simi-larlyassociated with inﬂammation or im-mune activation: greater high-sensitivityC-reactive protein (hsCRP) levels andgreaterT-cellactivation(deﬁnedasanin-creased percentage of T cells expressingCD38 and HLA-DR) were seen in sub-jects with HIV and human herpesvirus8 coinfection [13], and elevated levels ofinterleukin 6 (IL-6) and tumor necrosisfactor α (TNF-α) were associated withhigher levels of cytomegalovirus (CMV)immunoglobulininolder,HIV-uninfectedpopulations [14]. Microbial translocationpersiststosomedegreedespitesuppressiveARTand is associated with both immuneactivationandinﬂammation[15,16].Life-style factors (eg, smoking, sedentary hab-its, or injection drug use) can furtherincrease levels of immune activation andinﬂammation: HIV-infectedsmokers hadhigher T-cell activation, sCD14 levels,and lipopolysaccharide levels than HIV-infected nonsmokers, [17]; increased in-jection drug frequency in a cohort withoratriskforHIVinfectionwasassociatedwith higher IL-6 and CRP levels [18].Whether concomitant comorbidities arethe consequence or cause is a matter ofdebate, but heightened levels of inﬂam-mation and immune activation duringHIV infection are associated with severaldiseases, including depression [19], obesity[20],and diabetes [21].In previous studies, interventions toattenuate in ﬂammation and immune acti-vationhavetargetedsomeoftheinﬂamma-tion-associated factors mentioned above.For instance, treatment with valganciclovir,which has broad antiviral activity againstherpesviruses, including CMV, led to a de-creaseinCD8