The relationship between plasma and lymph node HIV-1 RNA levels has been well described, with similar resistance mutation patterns observed in HIV isolated from these two compartments [1]. The analysis of viral load and resistance patterns in the CSF, a well-recognized anatomically distinct compartment, is an area of active investigation. This work may have important implications regarding the effectiveness of antiretroviral drugs with significant CNS penetration for the prevention or treatment of HIV encephalitis and/or opportunistic infections that affect the CNS. A less well-appreciated tissue compartment, with very important implications for the sexual transmission of HIV, is the male and female genitourinary tract.

Although there is an association between HIV-1 levels in plasma and genital secretions (semen and cervicovaginal fluid), there is variability in the ability to isolate HIV-1 RNA from genital secretions at different time points between individuals [2,3]. For example, Mostad evaluated cervical and vaginal secretions throughout the menstrual cycle in 17 women (21-31 sample times per subject). She found HIV-infected cells in 4% to 100% of the total endocervical swabs and 0% to 71% of the total vaginal swabs obtained from each woman [4].

Significant discordance in both the detection and quantification of blood plasma and seminal plasma/cell HIV-1 RNA and culture has also been demonstrated [4]. Vernazza et al described 28 patients with detectable HIV-1 RNA in both semen and blood, with only 12 subjects showing levels within 1 log of each other. A similar proportion of subjects demonstrated a quantification discordance of greater than 10-fold in each direction. While the majority of cases with discordant detection results in blood and genital secretion compartments show plasma viremia without detectable genital secretion HIV-1 RNA, cases of detectable genital secretion (cervicovaginal fluid and semen) HIV-1 RNA in individuals with undetectable plasma HIV-1 RNA levels have been described [2,5,6]. Kiessling et al have also described cases of culturable virus in semen from men who did not have culturable virus in blood [5].

Another piece of evidence supporting the concept of genital secretion compartmentalization is the observation of sexual transmission of minor HIV variants based on HIV-1 gp120 sequence analysis [7]. Zhu et al evaluated five acute seroconverters and their sexual partners (transmitters). They observed sequence variation between the blood and genital secretions in all of the transmitters. They also describe the probable transmission of both cell-free (seminal plasma) and cell-associated virus. In one case, the HIV-1 quasispecies in the transmitter¹s plasma, the recipient¹s plasma and the recipient¹s vaginal secretions were all distinct.

Differential evolution of drug-resistant variants between compartments has been documented [5,8]. Depasquale et al described 10 patients treated with amprenavir-based antiretroviral regimens. In two patients, increased HIV-1 RNA levels and blood and seminal plasma were associated with similar mutations (L10I and I50V). In two other patients, HIV-1 rebound was associated with resistance mutations only in blood plasma. Keissling et al described two patients with differential evolution of PI resistance mutations over time, with fewer drug-associated mutations in seminal HIV-1 than in blood virus [5]. The mechanisms of differential resistance evolution between these compartments are not well understood. PI-resistant variants may penetrate into genital secretions poorly. Alternatively, poor penetration of PIs into macrophage-rich tissues, like brain and the testicles, may eliminate drug selection pressures in these compartments .

Implications: Providers and patients must understand that effective antiretroviral therapy may reduce plasma HIV-1 RNA levels to undetectable levels with ultra-sensitive assays, and still leave infectious virus remaining in genital secretions. While sexual transmission on a population basis is likely to decrease with widespread use of effective antiretroviral therapy, individual infectiousness and transmissibility are highly variable across patients and even within patients over time. Increases in rectal gonorrhea rates and other measures of increased risk activities among sexually active adults may be influenced by a lack of appreciation of the discordance between HIV-1 RNA levels and resistance patterns in these compartments.