There are several limitations to this model. First, the model was constructed with available biological data. Collection of semen specimens is difficult, and many potential subjects were excluded from consideration because they were receiving antiretroviral therapy. Second, our approach to the phenotypic requirements for HIV-1 transmission is flawed. We focused entirely on the NSI/SI phenotype whereas many other virologic properties might affect transmission . Furthermore, our assumption that only NSI isolates can be transmitted is not entirely correct, as SI variants have occasionally been sexually transmitted under some conditions . In addition, we assumed that the isolates in semen are similar to those in blood , but the SI/NSI ratio in the HIV-1 swarm in semen is unknown . In addition, we would expect to detect a higher proportion of SI isolates in subjects with more advanced disease [42,43]. Third, seminal plasma HIV-1 RNA levels were measured using two different techniques [22,24]. However, a recent study suggests that the seminal and blood HIV-1 RNA measurements used by these laboratories are comparable .
The greatest limitation of this and other models lies in the tremendous difficulty in clinical validation. Proving the model to be correct requires examination of the concentration of HIV-1 in semen actually leading to transmission of the virus in a discordant couple. A recent study in Uganda  has provided an exceptional opportunity for further examination of the predictions in the model. Quinn et al. measured HIV-1 in the blood of more than 15 000 study subjects, ultimately demonstrating that 415 HIV-1 infected subjects (228 infected men) were in discordant sexual partnerships. HIV-1 was not transmitted by infected subjects with less than 1500 copies of HIV-1 RNA/ml serum, whereas subjects with more than 50 000 copies HIV-1 RNA/ml serum infected sexual partners at a rate of 23 per 100 person-years over 30 months. While blood and semen clearly reside in separate and distinct biological compartments, blood viral burden can be correlated with viral burden in semen [22–24,46]. In addition, genital tract inflammation (which was commonly detected in the study in Uganda [45,47]) can increase HIV-1 in genital secretions to a level considerably greater than the level in blood . The transmission frequency observed in the Ugandan study strongly suggests that the increased transmission predicted at higher concentrations of HIV-1 in semen our model must have occurred.
Prevention of transmission of HIV-1 has proven a daunting task, in part because of confusion about the benefits to be derived from different approaches. Blower and coworkers have developed an important mathematical model designed to address the effects of antiretroviral therapy on the HIV-1 epidemic . This model is limited, however, by lack of empirical data. The probabilistic model presented here is actually developed around biological results. The model can be used to predict the effects of differences in semen viral burden and CCR5 receptors on HIV-1 transmission. Indeed, we and others have reported considerable variability in the concentration of HIV-1 in semen resulting from anatomical and physiological barriers between blood and the male genital tract, local genital tract replication of HIV-1 (which is greatly influenced by inflammation and sexually transmitted diseases) and the effects of antiviral therapy [5,37,48]. In addition, CCR5 receptor density is affected by a variety of factors [20,26]. Such variation may offer a biological basis for the accelerated spread of HIV-1 in some developing countries . In addition, this model can be used to predict the effects of biological interventions designed to reduce viral burden, influence viral phenotype, and/or expression of receptor cells.
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