Secondary Logo

Journal Logo


Role of viral replication, antiretroviral therapy, and immunodeficiency in HIV-associated atherosclerosis

Hsue, Priscilla Ya; Hunt, Peter Wb; Schnell, Amandaa; Kalapus, S Craiga; Hoh, Rebeccab; Ganz, Petera; Martin, Jeffrey Nb,c; Deeks, Steven Gb

Author Information
doi: 10.1097/QAD.0b013e32832b514b
  • Free



The number of people aged 50 and older living with HIV in the U.S. has increased 77% from 2001 to 2005 (, accessed on May 22). As the HIV-infected population continues to age, cardiovascular disease will become an increasingly important issue. This is particularly true as emerging data indicate that even after controlling for traditional risk factors (including age), HIV-infected patients have higher rates of atherosclerosis than HIV-seronegative persons [1,2]. Several factors may contribute to this risk, including direct antiretroviral drug toxicity [3,4]. Other possible contributing factors include HIV-associated inflammation and/or immunodeficiency, as well as direct effects of HIV replication on the endothelium. In a large randomized clinical study comparing continuous antiretroviral therapy to intermittent antiretroviral therapy (the SMART study), interrupting therapy (or not starting therapy) was associated with a higher risk of cardiovascular events [5], suggesting that any of these HIV-associated factors (viral replication, immunodeficiency, inflammation) may be causally associated with premature cardiovascular disease.

Chronic inflammation and immune activation are now recognized as major risk factors for atherosclerosis [6]. Since the immune system is chronically activated in untreated and to a lesser degree treated HIV disease [7], we recently postulated that T-cell activation is associated with atherosclerosis. Although T-cell activation assessed broadly did not correlate with carotid artery intima-media thickness (IMT), a validated measure of atherosclerosis, we found that cytomegalovirus (CMV) -specific CD8+ T-cell responses – which are greatly augmented in HIV disease – were strongly predictive of IMT [8]. These data provided support for an inflammatory/immune component as a mechanism for the accelerated atherosclerosis in HIV-infected individuals. Consistent with this theory, untreated HIV infection has been associated with increased levels of interleukin-6 (IL-6), a proinflammatory cytokine and a stimulus to hepatic C-reactive protein (CRP) production. Higher levels of IL-6 strongly predict cardiovascular events and overall mortality in antiretroviral-untreated and treated HIV infection [9]. Considered together, these observations suggest that HIV disease drives premature heart disease via its impact on the immune system and ultimately inflammation. Whether this immunomodulatory and proinflammatory effect is mediated via the level of HIV viremia, the degree of CD4+ cell depletion, or other processes remains unclear.

There exists among the HIV-infected population a rare group of individuals who are able to maintain undetectable plasma HIV RNA levels in the absence of any antiretroviral therapy. These ‘elite’ controllers are of high interest scientifically, as one of the primary objectives of a preventive HIV vaccine is to alter the host/virus interaction so that viremia remains low in those who become infected [10,11]. Although the mechanism of virus control in these individuals remains to be defined, it is clear that a strong and persistent HIV-specific immune response exists among these patients [12]. Indeed, we have demonstrated that the level of chronic immune activation is elevated among elite controllers as compared to HIV negatives [13]. Controllers are enriched for a number of genetic polymorphisms that affect the inflammatory response [14,15].

In order to test the importance of antiretroviral therapy, viral replication, immunodeficiency, and inflammation in driving atherosclerosis, we assessed carotid IMT, a measure of atherosclerosis, and CRP, a measure of systemic inflammation, in a diverse group of HIV-uninfected and infected adults. Because the HIV controllers lack both exposure to antiretroviral therapy and have neither measurable viremia nor overt immunodeficiency, we focused on these persons to determine if they are prone to premature atherosclerosis and if so, whether HIV-associated inflammatory responses might be contributory. Accordingly, these HIV controllers were compared to four relevant comparator groups: HIV-seronegative adults, untreated HIV-seropositive adults with detectable levels of viral replication and HIV-seropositive adults receiving long-term antiretroviral therapy both with and without detectable levels of viral replication.


Study participants

All study participants were recruited from the University of California, San Francisco SCOPE Cohort. By design, nested within this cohort is a relatively large group of rare individuals who were recruited on the basis of their ability to control HIV replication in the absence of therapy. Individuals are referred to SCOPE and this substudy independently of their cardiovascular risk. All individuals underwent a standard interview and had high-resolution ultrasound measurement of carotid IMT. For the purposes of the current analysis, participants were classified on the basis of their HIV disease and treatment status at the time of the ultrasound studies into four groups: HIV controllers: positive for HIV by standard antibody serological determinations with undetectable HIV RNA level (<75 copies RNA/ml) in absence of therapy, HIV noncontrollers: detectable HIV RNA levels in absence of therapy, highly active antiretroviral therapy (HAART) responders: on combination antiretroviral therapy with undetectable HIV RNA levels, and HAART nonresponders: on combination therapy with persistently detectable HIV RNA levels. HIV-seronegative participants were selected mainly from those answering advertisements to participate in research studies who were similar in age and sex to the HIV-infected participants. The University of California, San Francisco Committee on Human Research approved the study, and all patients provided written informed consent.

Risk factor assessment

All patients underwent a detailed interview and structured questionnaire given by study investigators covering sociodemographic characteristics, HIV disease history, other comorbid conditions, health-related behaviors, medication exposure, and family history. Detailed chart review was performed on each patient to carefully ascertain duration of antiretroviral medication. Total and High-density lipoprotein (HDL) cholesterol, triglycerides, high-sensitivity CRP (hsCRP; Dade Behring), and glucose were measured from blood obtained in the fasting state. Low-density lipoprotein (LDL) cholesterol was calculated except in hypertriglyceridemic patients (triglycerides >400 mg/dl) in whom it was measured directly.

Carotid intima-media thickness measurements

Carotid IMT was measured by high-resolution ultrasound with the GE VividSeven Imaging System and a 10-MHz linear array probe, as described previously [1]. Briefly, carotid IMT was measured in 12 predefined segments (six segments per side) using the standardized protocol of the Atherosclerosis Risk in Communities (ARIC) Study which includes measurements of the near and far wall of the common carotid, the carotid bifurcation, and the internal carotid [16–18]. Mean value of 12 segments was calculated. All scans were performed and measurements obtained on digital images using manual calipers by a single experienced vascular technician who was blinded to the participant's HIV status and treatment status. Fifteen patients underwent a second carotid scan within 1 month of the first. The correlation coefficient for the comparison of blinded measurements was greater than 0.90.

Statistical analyses

Unadjusted comparisons between groups were made with Kruskal–Wallis tests followed by pairwise Wilcoxon rank sum tests for continuous variables and chi-square and Fisher's exact tests for categorical variables. Correlations between continuous variables were assessed with Spearman's rank correlation coefficients. Adjusted differences between groups were assessed with linear regression, transforming continuous variables and calculating standard errors with heteroskedasticity-consistent covariance matrix estimators when necessary to satisfy model assumptions [19]. All traditional cardiac risk factors [age, sex, family history, hypertension, fasting serum glucose, smoking (in pack years), and LDL level] were considered as potential confounders in multivariable models. In addition, we explored the relationship between other potential predictors of IMT as possible confounders including current use of lipid-lowering therapy, mean arterial blood pressure, and fasting serum triglycerides, and HDL on the day of evaluation, considering each of these factors in multivariable models if they were associated with IMT in unadjusted models at the P < 0.10 level. All traditional risk factors as well as those additional factors associated with IMT in unadjusted analyses were initially included in multivariable models, then removed in a stepwise manner if their inclusion changed the beta coefficient of the primary predictor (controllers vs. control group) by less than 10%. Since hsCRP may be a mediator of HIV-associated atherosclerosis rather than a true confounder, we assessed models with and without hsCRP.


Participant characteristics

The characteristics of the 401 HIV-seropositive participants, including 33 HIV controllers, as well as 93 HIV-seronegative controls are shown in Table 1. Most of the study participants were men (87% in the HIV-infected group and 77% of controls, respectively) and approximately 50% were Caucasian. The HIV-seropositive patients were older than the controls (48 years compared to 43 years) and more likely to have smoked in the past. The HIV-seropositive patients were also more likely to have had a prior history of coronary artery disease and a prior history of hypertension, whereas the controls had a higher LDL cholesterol and HDL cholesterol (Table 1). The median duration of HIV diagnosis ranged from 11 to 15 years, and was similar in each of the four HIV-seropositive groups (Table 1). The median nadir CD4+ cell count for HIV controllers, noncontrollers, HAART responders, and HAART nonresponders was 491, 361, 110, and 70 cells/μl, respectively. Most of the antiretroviral-treated patients had received protease inhibitors for part or all of their treatment course. The median duration of HAART was 5.8 years in the responders and 4.9 years in nonresponders.

Table 1
Table 1:
Coronary risk factors and laboratory values in HIV-infected and uninfected persons.

Traditional risk factors in HIV-associated atherosclerosis

As has been reported by our group and others in the past, HIV-seropositive participants had much higher median IMT than HIV-seronegative participants (0.91 vs. 0.72 mm, P < 0.001; see Fig. 1). Among all participants, increasing age, cigarette pack years, LDL cholesterol, triglycerides, current lipid lowering therapy use, glucose (but not diabetes), hypertension, and hsCRP were each associated with higher IMT. However, the difference in the carotid IMT between the HIV-seropositive and seronegative individuals remained highly significant even after adjusting for all these risk factors, as well as family history and sex (P < 0.001).

Fig. 1
Fig. 1:
Comparison of carotid IMT in HIV-infected and uninfected individuals. Antiretroviral-untreated patients with undetectable viral loads (HIV controllers) had a higher median carotid IMT than the HIV-seronegative persons, even after controlling for traditional risk factors. Carotid IMT was comparable in the HIV controllers and untreated HIV noncontrollers. ART+, on antiretroviral therapy; ART, not on antiretroviral therapy; IMT, intima-media thickness; VL < 75, undetectable HIV RNA; VL > 75, detectable HIV RNA; VL, viral load.

Carotid IMT is increased in HIV controllers

Despite having no exposure to antiretroviral therapy, no detectable HIV RNA levels using conventional assays, and high CD4+ T-cell counts, the HIV controllers had a higher median IMT than the HIV-seronegative participants (0.91 vs. 0.72 mm, P < 0.001). This difference remained significant when stratifying by smoking, hypertension, or age (Fig. 2). The difference also remained significant when restricting the analysis to those with a current CD4+ cell count more than 500 cells/μl (Fig. 2). The HIV controllers also had higher adjusted mean IMT than HIV-uninfected participants after controlling for traditional risk factors in a multivariable linear regression analysis (P = 0.005; Table 2). This difference remained significant even when restricting the multivariable model to those without hypertension and to those with CD4 cell counts more than 500 cells/μl (P = 0.031).

Fig. 2
Fig. 2:
IMT in HIV controllers and HIV-seronegative persons stratified by potential confounders. Carotid IMT was higher in HIV controllers than HIV-seronegative persons when stratified by age (panel a), the presence or absence of hypertension (panel b), and a history of tobacco smoking (panel c). Carotid IMT was also higher among the controllers than HIV-seronegative persons even after restricting the analysis to those with CD4+ T-cell counts above 500 cells/μl (panel d). IMT, intima-media thickness.
Table 2
Table 2:
IMT in HIV controllers and HIV-uninfected individuals after adjustment for traditional cardiac risk factors.

CD4+ cell counts, plasma HIV RNA levels, and carotid IMT

The HIV controllers also had a trend toward higher median IMT than HIV-infected noncontrollers (0.91 vs. 0.83 mm, P = 0.13; Fig. 1), suggesting that high levels of HIV replication and/or immunodeficiency evidenced by reduced CD4+ cell counts are not a prerequisite for the development of atherosclerosis in the setting of untreated HIV infection. In fact, higher plasma HIV RNA levels were weakly associated with lower IMT among the HIV noncontrollers (rho −0.23, P = 0.022), although this relationship was no longer significant after adjustment for age (P = 0.69). In addition, there was no evidence for a difference in IMT between HIV controllers and either HAART responders (P = 0.49) or nonresponders (P = 0.86). There was also no evidence for a relationship between IMT and CD4+ T-cell count among HIV controllers (rho 0.23, P = 0.20) or untreated noncontrollers (rho 0.13, P = 0.20). Finally, there was no evidence for a relationship between IMT and self-reported nadir CD4+ T-cell count among treated HIV-infected participants.

Antiretroviral treatment and carotid IMT

Antiretroviral-treated patients had a higher median IMT than the untreated patients (0.94 vs. 0.85 mm, P = 0.006; Fig. 3). Furthermore, among all HIV-infected participants, increasing duration of HAART (rho 0.20, P < 0.001), protease inhibitor use (rho 0.19, P < 0.001), and nucleoside analogue use (rho 0.23, P < 0.001) were each associated with thicker IMT. These relationships remained significant after adjustment for traditional cardiac risk factors and the duration of HIV diagnosis (P ≤ 0.024 for all).

Fig. 3
Fig. 3:
Effect of HAART on carotid IMT. Carotid IMT was higher in patients who were receiving HAART than in either antiretroviral untreated patients or HIV-seronegative persons. The effect of HAART remained significant after controlling for traditional risk factors. HAART, highly active antiretroviral therapy; IMT, intima-media thickness.

C-reactive protein is increased in HIV controllers

High-sensitivity C-reactive protein values were significantly higher among all HIV-seropositive patients compared to HIV-seronegative controls (median value of 2 mg/dl in HIV-seropositive vs. 1.1 mg/dl in HIV-seronegative, P < 0.001; see Table 1). This was true even after correcting for traditional risk factors (P = 0.003). Notably, hsCRP in the HIV controllers was similar to each of the other HIV-infected groups (Kruskal–Wallis test, P = 0.85). Although CRP was elevated in our controllers, it did not appear to explain the difference in IMT between the controllers and the HIV-seronegative persons since inclusion of hsCRP in the multivariable model changed the adjusted difference between HIV controllers and HIV-seronegative persons by less than 10% and the difference between controllers and HIV-seronegative persons remained significant (P = 0.003).


HIV-infected patients are at an increased risk of developing atherosclerosis and cardiovascular disease than age-matched HIV-seronegative adults, yet the mechanisms accounting for this effect remain poorly defined. To clarify the role of several factors putatively associated with atherosclerosis in HIV patients, we used high-resolution ultrasound to quantify subclinical atherosclerosis in a large cohort of HIV-infected individuals. Nested within this cohort was a sizeable group of HIV-seropositive individuals who are able to maintain an undetectable HIV viral load in the absence of antiretroviral therapy (elite controllers). Compared to uninfected controls, carotid IMT was higher among all groups of HIV patients, irrespective of antiretroviral treatment or the level of viremia. HIV controllers were of particular interest as they lacked the previously suggested key risk factors needed for the development of HIV-associated atherosclerosis namely, exposure to antiretroviral therapy, high-level viremia, and/or advanced immunodeficiency. The unexpected finding of a high IMT in HIV controllers suggests that other factors contribute to the pathogenesis of HIV-associated atherosclerosis. We have previously reported that ‘elite’ control of HIV is typically associated with high levels of T-cell activation (as compared to HIV-seronegative persons) [8], and extend these observations to include CRP, a marker of systemic inflammation. Collectively, these data argue for a possible role of persistent HIV-associated inflammation as a potential cause for accelerated atherosclerosis in HIV disease.

One potential explanation for our findings was that we inadvertently selected a group of HIV-seronegative controls who lacked risk factors and/or had unusually low levels of IMT. This is unlikely as our seronegative controls had carotid IMT values between the 50th and 75th percentile of the Multi-Ethnic Study of Atherosclerosis Study cohort aged 45–54 years, whereas our HIV controllers had IMT values far in excess of 75th percentile of this cohort [20]. In fact, the IMT of our HIV-infected patients, including that of the HIV controllers, was similar to that of patients with heterozygous familiar hypercholesterolemia before the era of intensive statin use [21], a condition almost invariably associated with premature atherosclerosis and coronary heart disease. Our findings suggest that HIV may be associated with a similarly accelerated form of atherosclerosis.

Although ‘elite’ controllers lack readily detectable HIV RNA using conventional assays, they clearly harbor replication-competent virus and almost invariably have measurable plasma HIV RNA using very sensitive assays [22,23]. Determining the degree to which this low-level HIV replication among HIV controllers is responsible for increased cardiovascular risk has implications for antiretroviral-treated patients, since they too often have evidence of persistent low-level viremia (and perhaps low-level viral replication) [24–26].

Among HIV controllers, CRP levels, a marker of systemic inflammation, are elevated and indistinguishable from that of the other HIV-seropositive groups. In uninfected patients, atherosclerosis is a disease with a strong proinflammatory component [6]. Activated T-cells, macrophages, and mast cells act in concert to release factors leading to atherosclerosis initiation, progression, plaque instability, and intraluminal thrombus formation [6]. Within the context of HIV infection, heightened antigen-specific T-cell responses and more recently levels of IL-6, a key stimulus to the hepatic production of CRP, have been associated with accelerated atherosclerotic disease [8,9]. Here, we used measurements of hsCRP to confirm that HIV disease is a proinflammatory state, even among the HIV controllers. In uninfected individuals, hsCRP independently predicts cardiovascular disease risk [27,28], whereas in HIV-seropositive patients, hsCRP clearly predicts mortality [29]. Although the presence of relatively high hsCRP levels in our controllers confirms that long-term host-mediated control of HIV is a proinflammatory state, the fact that CRP only explained a small proportion of the differences in IMT between the HIV controllers and HIV-seronegative persons suggests that other inflammatory mediators are more likely causally associated with premature atherosclerosis in HIV disease.

Several factors may contribute to systemic inflammation in HIV-infected controllers. First, HIV infection is associated with an early and rapid destruction of CD4+ T-cell population within the intestinal lymphoid tissue [30]. This loss of antimicrobial defense mechanism may lead to the chronic entry of bacterial proinflammatory products including endotoxin (lipopolysaccharide) into the blood stream (bacterial translocation) [31]. We have demonstrated that compared to controls, HIV controllers (as well as HIV noncontrollers) have much higher circulating levels of lipopolysaccharide [13] a product associated with endothelial dysfunction [32,33] and early atherogenesis [34]. Increases in lipopolysaccharide also activate the innate and adaptive immune systems [31]. Accordingly, higher levels of bacterial lipopolysaccharide potentially result in endothelial dysfunction, immune activation, and chronic inflammation leading to accelerated atherosclerosis among individuals with HIV, including HIV controllers. Second, other viruses in patients with HIV may be involved in immune activation and inflammation and hence atherosclerosis. Most HIV patients, including controllers, are seropositive for CMV. Among all HIV patients, we have shown that increases in CMV-specific T-cell responsiveness correlate directly with the extent of atherosclerosis [8]. In preliminary data from our group, HIV controllers appear to have higher CMV-specific T-cell responses compared to uninfected controls (Hunt P-W, unpublished data), suggesting that inflammatory responses related to CMV infection may play a role in HIV-associated atherosclerosis. Lastly, strong HIV-specific T-cell responses – the very responses that are thought to help controllers maintain control of HIV replication – [12,35–40] may also be contributing to generalized inflammation even in the absence of clinically detectable viremia [41].

The study has several limitations that deserve comment. This was a cross-sectional study, in which the rate of progression in carotid IMT cannot be measured. This study design makes it particularly challenging to compare treated and untreated disease, as those on and off therapy almost certainly have very different prior disease histories that are difficult to measure. The comparisons between the HIV-seronegative persons and the HIV controllers are less problematic, as the two groups likely differ primarily in the exposure variable of interest. Also, the magnitude of the differences between the HIV-seronegative persons and the controllers is so great that unmeasured confounders are unlikely to solely account for our observed differences. Another potential limitation is the absence of studies correlating carotid IMT with cardiovascular event rates in the HIV infected population. However, extensive data [20] suggest that carotid IMT is a powerful predictor of cardiovascular outcomes in patients without HIV. Extrapolation to HIV patients is reasonable, although remains to be proven. Finally, it is important to stress that the role of inflammation in causing the relatively high levels of IMT in our controllers is based largely on inferences from our prior studies in which we demonstrate that long-term host-mediated control of HIV replication is associated with high levels of T-cell activation. We plan in future studies to investigate in more detail the relationship between inflammation and IMT progression among a larger number of HIV controllers. Larger studies will also allow us to control for other potential factors that might be related to persistent inflammation in HIV-infected controllers, including injection drug abuse and/or the presence of certain other coinfections (e.g. CMV, hepatitis B virus, hepatitis C virus).

In summary, HIV infection is associated with premature atherosclerosis, as measured by IMT. This occurs even in the absence of detectable viremia, overt immunodeficiency, and exposure to antiretroviral therapy, and appears to be independent of traditional cardiac risk factors. Whereas antiretroviral therapy and advanced immunodeficiency likely contribute independently to atherosclerosis in HIV patients, our results with the controllers demonstrate that these elements are not a prerequisite for higher levels of subclinical atherosclerosis. Whether the premature atherosclerosis observed in our controllers is due directly to an inflammatory process remains to be established. From a clinical perspective, our observations suggest that all HIV-infected individuals – even those doing apparently well with or without antiretroviral treatment – may benefit from aggressive cardiovascular risk management and perhaps the use of anti-inflammatory agents such as statins [42], although this remains unproven treatment in this setting. Finally our observations have implications for individuals treated adequately with antiretroviral therapy by current standards, since it remains possible that persistent low-level viral replication which can occur despite otherwise effective therapy may still prove to be harmful. In the future, achieving and maintaining even lower viral loads than current therapies permit in individuals with HIV will need to be investigated both in terms of HIV disease and cardiovascular risk.


Sources of funding: Dr Hsue is a recipient of a Clinical Scientist Development Award from the Doris Duke Charitable Foundation, a Grant-in-Aid from the American Heart Association, and a grant from the NIH (K23A1066885). This work was supported in part by the UCSF/Gladstone Center for AIDS Research (P30 AI27763, P30 MH59037), NIAID (AI055273, AI44595, K23AI065244, K24AI069994), the Center for AIDS Prevention Studies (P30 MH62246), the UCSF Clinical and Translational Science Institute (UL1 RR024131-01), and American Foundation for AIDS Research (106710-40-RGRL).

Presented in part at the 15th Conference on Retroviruses and Opportunistic Infections, Boston, MA February 3-6, 2008 and at the 57th Annual Scientific Session of the American College of Cardiology, Chicago, IL March 29-April 1, 2008.


1. Hsue PY, Lo JC, Franklin A, Bolger AF, Martin JN, Deeks SG, Waters DD. Progression of atherosclerosis as assessed by carotid intima-media thickness in patients with HIV infection. Circulation 2004; 109:1603–1608.
2. Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with HIV disease. J Clin Endocrinol Metab 2007.
3. Friis-Moller N, Sabin CA, Weber R, d'Arminio Monforte A, El-Sadr WM, Reiss P, et al. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 2003; 349:1993–2003.
4. Sabin CA, Worm SW, Weber R, Reiss P, El-Sadr W, Dabis F, et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multicohort collaboration. Lancet 2008; 371:1417–1426.
5. El-Sadr WM, Lundgren JD, Neaton JD, Gordin F, Abrams D, Arduino RC, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006; 355:2283–2296.
6. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352:1685–1695.
7. Hunt PW, Martin JN, Sinclair E, Bredt B, Hagos E, Lampiris H, Deeks SG. T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy. J Infect Dis 2003; 187:1534–1543.
8. Hsue PY, Hunt PW, Sinclair E, Bredt B, Franklin A, Killian M, et al. Increased carotid intima-media thickness in HIV patients is associated with increased cytomegalovirus-specific T-cell responses. AIDS 2006; 20:2275–2283.
9. Kuller LH, Tracy R, Belloso W, De Wit S, Drummond F, Lane HC, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med 2008; 5:e203.
10. Walker BD, Burton DR. Toward an AIDS vaccine. Science 2008; 320:760–764.
11. Deeks SG, Walker BD. Human immunodeficiency virus controllers: mechanisms of durable virus control in the absence of antiretroviral therapy. Immunity 2007; 27:406–416.
12. Emu B, Sinclair E, Favre D, Moretto WJ, Hsue P, Hoh R, et al. Phenotypic, functional, and kinetic parameters associated with apparent T-cell control of human immunodeficiency virus replication in individuals with and without antiretroviral treatment. J Virol 2005; 79:14169–14178.
13. Hunt PW, Brenchley J, Sinclair E, McCune JM, Roland M, Page-Shafer K, et al. Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J Infect Dis 2008; 197:126–133.
14. Martin MP, Qi Y, Gao X, Yamada E, Martin JN, Pereyra F, et al. Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1. Nat Genet 2007; 39:733–740.
15. Dolan MJ, Kulkarni H, Camargo JF, He W, Smith A, Anaya JM, et al. CCL3L1 and CCR5 influence cell-mediated immunity and affect HIV-AIDS pathogenesis via viral entry-independent mechanisms. Nat Immunol 2007; 8:1324–1336.
16. Chambless LE, Heiss G, Folsom AR, Rosamond W, Szklo M, Sharrett AR, Clegg LX. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) Study, 1987–1993. Am J Epidemiol 1997; 146:483–494.
17. Heiss G, Sharrett AR, Barnes R, Chambless LE, Szklo M, Alzola C. Carotid atherosclerosis measured by B-mode ultrasound in populations: associations with cardiovascular risk factors in the ARIC study. Am J Epidemiol 1991; 134:250–256.
18. Wu KK, Folsom AR, Heiss G, Davis CE, Conlan MG, Barnes R. Association of coagulation factors and inhibitors with carotid artery atherosclerosis. Early results of the Atherosclerosis Risk in Communities (ARIC) Study. Ann Epidemiol 1992; 2:471–480.
19. Davidson R, MacKinnon J. Estimation and inference in econometrics. New York: Oxford University Press; 1993.
20. Stein JH, Korcarz CE, Hurst RT, Lonn E, Kendall CB, Mohler ER, et al. Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force. Endorsed by the Society for Vascular Medicine. J Am Soc Echocardiogr 2008; 21:93–111, quiz 189–190.
21. Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet 2001; 357:577–581.
22. Blankson JN, Bailey JR, Thayil S, Yang HC, Lassen K, Lai J, et al. Isolation and characterization of replication-competent human immunodeficiency virus type 1 from a subset of elite suppressors. J Virol 2007; 81:2508–2518.
23. Hatano H, Delwart EL, Norris PJ, Lee TH, Dunn-Williams J, Hunt PW, et al. Evidence for persistent low-level viremia in individuals who control human immunodeficiency virus in the absence of antiretroviral therapy. J Virol 2009; 83:329–335.
24. Chun TW, Nickle DC, Justement JS, Large D, Semerjian A, Curlin ME, et al. HIV-infected individuals receiving effective antiviral therapy for extended periods of time continually replenish their viral reservoir. J Clin Invest 2005; 115:3250–3255.
25. Havlir DV, Strain MC, Clerici M, Ignacio C, Trabattoni D, Ferrante P, Wong JK. Productive infection maintains a dynamic steady state of residual viremia in human immunodeficiency virus type 1-infected persons treated with suppressive antiretroviral therapy for five years. J Virol 2003; 77:11212–11219.
26. Ramratnam B, Mittler JE, Zhang L, Boden D, Hurley A, Fang F, et al. The decay of the latent reservoir of replication-competent HIV-1 is inversely correlated with the extent of residual viral replication during prolonged antiretroviral therapy. Nat Med 2000; 6:82–85.
27. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336:973–979.
28. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002; 347:1557–1565.
29. Lau B, Sharrett AR, Kingsley LA, Post W, Palella FJ, Visscher B, Gange SJ. C-reactive protein is a marker for human immunodeficiency virus disease progression. Arch Intern Med 2006; 166:64–70.
30. Mehandru S, Poles MA, Tenner-Racz K, Manuelli V, Jean-Pierre P, Lopez P, et al. Mechanisms of gastrointestinal CD4+ T-cell depletion during acute and early human immunodeficiency virus type 1 infection. J Virol 2007; 81:599–612.
31. Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 2006; 12:1365–1371.
32. Bhagat K, Moss R, Collier J, Vallance P. Endothelial ‘stunning’ following a brief exposure to endotoxin: a mechanism to link infection and infarction? Cardiovasc Res 1996; 32:822–829.
33. Bhagat K, Vallance P. Inflammatory cytokines impair endothelium-dependent dilatation in human veins in vivo. Circulation 1997; 96:3042–3047.
34. Wiedermann CJ, Kiechl S, Dunzendorfer S, Schratzberger P, Egger G, Oberhollenzer F, Willeit J. Association of endotoxemia with carotid atherosclerosis and cardiovascular disease: prospective results from the Bruneck Study. J Am Coll Cardiol 1999; 34:1975–1981.
35. Betts MR, Nason MC, West SM, De Rosa SC, Migueles SA, Abraham J, et al. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 2006; 107:4781–4789.
36. Harari A, Petitpierre S, Vallelian F, Pantaleo G. Skewed representation of functionally distinct populations of virus-specific CD4 T cells in HIV-1-infected subjects with progressive disease: changes after antiretroviral therapy. Blood 2004; 103:966–972.
37. Saez-Cirion A, Lacabaratz C, Lambotte O, Versmisse P, Urrutia A, Boufassa F, et al. HIV controllers exhibit potent CD8 T cell capacity to suppress HIV infection ex vivo and peculiar cytotoxic T lymphocyte activation phenotype. Proc Natl Acad Sci USA 2007; 104:6776–6781.
38. Pereyra F, Addo MM, Kaufmann DE, Liu Y, Miura T, Rathod A, et al. Genetic and immunologic heterogeneity among persons who control HIV infection in the absence of therapy. J Infect Dis 2008; 197:563–571.
39. Emu B, Sinclair E, Hatano H, Ferre A, Shacklett B, Martin JN, et al. HLA class I-restricted T-cell responses may contribute to the control of human immunodeficiency virus infection, but such responses are not always necessary for long-term virus control. J Virol 2008; 82:5398–5407.
40. Migueles SA, Osborne CM, Royce C, Compton AA, Joshi RP, Weeks KA, et al. Lytic Granule Loading of CD8(+) T Cells Is Required for HIV-Infected Cell Elimination Associated with Immune Control. Immunity 2008; 29:1009–1021.
41. Hunt PW, Sinclair E, Hatano H, McCune JM, Emu B, Tan QX, et al.Relationship between HIV-specific Immune Response, T Cell Activation, and CD4+ T Cell Depletion in HIV-infected Patients with Undetectable Plasma HIV RNA Levels in the Absence of Therapy. Program and Abstracts from the 15th Conference on Retroviruses and Opportunistic Infections, 2008, Boston, MA [Abstract # 353] 2008.
42. Nissen SE, Tuzcu EM, Schoenhagen P, Crowe T, Sasiela WJ, Tsai J, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005; 352:29–38.

atherosclerosis; carotid arteries; HIV controllers; HIV infection; immunodeficiency; inflammation

© 2009 Lippincott Williams & Wilkins, Inc.