The development of highly active antiretroviral therapies (HAART) led to the hope that regulation of immune status and viral replication may help to ameliorate HIV-associated subcortical brain changes and subsequent cognitive impairment, but data supporting this conjecture are mixed. For example, one study reported a hypertrophy of the PUT of HIV-infected individuals with mild cognitive dysfunction, with increased putamen volume related to decreased motor speed (Castelo et al. 2007). Another recent study (Paul et al. 2008) found similar associations but in the opposite direction, and the putamen was (on average) smaller in the HIV-infected individuals.

We then examined the relationship between HIV-associated factors and the summary volume. For these analyses the basal ganglia summary variable was dichotomized at the median of the HIV-infected participants only. The data were divided based on the group median because we were interested in examining the factors associated with atrophy in the HIV-infected men. We found no significant differences between the two groups of infected men in terms of their current CD4+ cell count or HIV viral load, or the nadir CD4+ cell count and peak HIV viral load (see Table 3). There was no effect of using antiretroviral medications with greater CNS penetrance on basal ganglia volume (Letendre et al. 2008). We did find a significant difference in the number of years of infection, such that here was a trend for the time since seroconversion (i.e., n=19) to be longer among the men with smaller basal ganglia; the effect size did not differ from that of the men with prevalent infection (i.e., r=.39 vs. r=.45) (See Supplementary Figure E-1). We regressed the basal ganglia summary volume on age, race, and time since first known seropositivity in all 84 HIV-infected men. Only the time variable was related to volume (β=−.48, t(83) = 4.20, p<.001), and neither age (β=−.11, p>.10) nor race (β=−.12, p>.10) were associated with basal ganglia volume. When we compared the HIV-infected men as a function of the time since first seropositivity (Table 4), only the summary basal ganglia volume and age differed among the groups (See also Supplemental Figure E-2).

Figure 1 shows the regions of the CDT and PUT where the mean radial size of these structures was lower in the HIV-infected than in the control group (See also Supplemental Figure E-3). The level of local atrophy was significantly associated with serostatus (all corrected p values, computed by permutation testing were less than 0.001, see Supplemental Table E-1). There were no regions of local expansion that reached statistical significance for either the caudate or the putamen.

First, the “time” variable reflects both incident infection (i.e., with a better estimate of date of infection) and prevalent infection (where the infection occurred at some time prior to enrollment in the MACS). The most parsimonious explanation of the time effect is that it is related to the enrollment of new recruits into the MACS. Volunteers entered in three waves: 1984/85, 1987/90, and in 2001/03 (primarily from racial/ethnic minorities); the men joining in 2001–2003 were generally already infected. The majority of our seropositive volunteers (57%) were either infected at the time of enrollment 25 years ago, or were infected soon thereafter. A smaller group became infected in the following 10 years of the study, and the remainder (27%) either entered the study with HIV infection or seroconverted during that time period. The group with the longest duration of infection will have had the longest time without any treatment, will have had some time with non-HAART monotherapy, and will have been among the group that managed to survive the infection. The group that became infected most recently had the opportunity to receive HAART as the first line of therapy, and likely had therapy initiated at an earlier point in the natural history of the infection. This interpretation suggests that earlier and more aggressive intervention may help protect the brain from long-term effects of the virus (Marcondes et al. 2009). However, a recent cross-sectional study (Cohen et al. 2010) that found that nadir CD4+ cell counts and duration of infection were related to cortical volume, whereas caudate nucleus volumes were related to current plasma viral load. When we examined the association between the current HIV viral load and basal ganglia volume among the men with measureable virus in plasma, the correlation was modest, at best (r=−.21, p=.33, n=23). The differences in the analysis technique, particularly the method of the spatial normalization of the scans, may be one source of difference between studies.

Alternatively, the effect of time may be the consequence of a low grade, chronic process that alters brain structure even when peripheral measures of viral load and immunocompetence are within acceptable limits (Chang et al. 2003; Chang et al. 2002; Ernst and Chang 2004). There may be an ongoing process related to HIV disease, which was not altered by the changing dynamics of the infection, and which may not be reflected in the clinical quiescent period (Cysique et al. 2005). Consistent with this idea was the finding that the regions of the basal ganglia that were significantly correlated with duration of infection were similar in both location and extent of contraction to those areas that were related to HIV disease overall. The major differences between the maps were in the local p-values, which were influenced by the sample size used for the two analyses.

We favor the first of these hypotheses in part because it is more parsimonious, but also because it seems to be more in line with the accumulating data that suggest that what we are observing is the damage done to the CNS prior to the initiation of HAART. For example, data from a study in China have found that while cognitive functions improve with anti-retroviral therapy, these patients did not return to normal (Cysique et al. 2010). Distinguishing between these two hypotheses is critical for understanding the effects of HIV on the CNS, and for developing rational treatment policies. However, this will require longitudinal data from HIV-infected individuals with a range of time-since-infection, and a substantial group with exposure only to HAART.

Several points should be considered when interpreting these data. The MACS Cardiovascular substudy was initiated in 2004 and included men age ≥40 years, with no self-reported history of clinical heart disease or cerebrovascular disease; all of the participants in this MRI study were at least 50 years old. Thus, these are individuals who, by and large, survived for 15–25 years with the virus, without developing significant age- and treatment-related comorbidities that are becoming increasingly common as the epidemic ages. None of the men in the study met criteria for HIV-Associated Dementia, although 9/84 (11%) performed in the mildly impaired range (i.e., asymptomatic impairment or minor neurocognitive disorder) (Antinori et al. 2007). Furthermore, we have noted previously (Becker et al. 2009), that the overall health of the HIV-infected men in this study is generally better than that of the seronegative control participants. Consequently, the men with HIV disease likely had fewer vascular risk factors for cognitive impairment and brain atrophy due to aggressive use of statins and anti-hypertensive medications, and they are also individuals who may have a different physiological resistance relative to individuals who succumbed to HIV. Finally, the HIV-infected men who were enrolled in the MACS in 2001–2003 and who were on HAART at the time that they enrolled also: a) had to have had a known date of HAART initiation, b) could not have had an AIDS diagnosis before (or coincident with) the initiation of HAART, and c) had to have had HIV RNA and CD4+ data within 4 months before HAART initiation. This means that those men who did not have as good access to care, or who were not as healthy were not included in this recruitment wave.

These findings are consistent with our prior studies using a different cohort of HIV-infected individuals who had poorer health-related outcomes. For example, we found significant bilateral brain atrophy that was correlated with cognitive impairment and CD4+ cell counts (Chiang et al. 2007), while others (Paul et al. 2008) report that the basal ganglia were smaller, although not significantly, among HIV + individuals. However, the younger age of that sample (mean ~38 years) suggests a shorter duration of infection, which may be linked to less volume loss. The findings of increased brain region size (Castelo et al. 2007) are more difficult to reconcile, and there may have been some differences in the sampling frame relative to the present study that may have accounted for the differences between the studies.

HIV viral proteins are neurotoxic, so the volumetric differences found here may reflect neuronal loss, reduced dendritic complexity, synaptic loss (Wiley et al. 1991), and associated white matter degeneration. HAART medications often fail to significantly penetrate the blood brain barrier (Cysique et al. 2004), so brain atrophy may still occur in patients treated with antiretroviral medication. The MACS has previously shown that levels of viremia and CD4+ cell count predict the onset of HIV-Associated Dementia and neuropathy prior to the use of HAART (Childs et al. 1999). The data that we present here suggest that the overall duration of infection may be an important predictor of the extent of CNS damage—even if viral load and CD4+ cell counts are currently under control. Our study participants who have been infected for more than 15 years would have suffered a progressive loss of gray and white matter, and specific loss in the CDT (Stout et al. 1998). With the advent of effective therapy, this loss may have slowed, but was not arrested. The use of medications with higher CNS penetrance would have offered greater, but not complete protection, to the CNS (Marra et al. 2003; Marra et al. 2009). Thus, we would expect that with earlier and better control of viral replication, the CNS complications of HIV disease, especially those related to CNS structure, will be greatly attenuated.