Epidemiology & Social
Viral burden in genital secretions determines male-to-female sexual transmission of HIV-1: a probabilistic empiric model
Chakraborty, Hrishikesh; Sen, Pranab K.a; Helms, Ronald W.a; Vernazza, Pietro L.b; Fiscus, Susan A.c; Eron, Joseph J.d; Patterson, Bruce K.e; Coombs, Robert W.f; Krieger, John N.g; Cohen, Myron S.d
From the Department of Biostatistics, Rollin School of Public Health, Emory University, Atlanta, Georgia, the aDepartment of Biostatistics, University of North Carolina at Chapel Hill, North Carolina, USA, the bDepartment of Medicine and Institute for Clinical Microbiology, Kantonsspital, St. Gallen, Switzerland, the Departments of cMicrobiology and Immunology and dMedicine, University of North Carolina at Chapel Hill, North Carolina, the eDepartment of Pediatrics/Infectious Diseases, Children's Memorial Hospital, Northwestern University Medical School, Chicago, Illinois, and the Departments of fLaboratory Medicine and gUrology, School of Medicine, Seattle, Washington, USA.
Received: 4 August 2000;
revised: 20 December 2000; accepted: 10 January 2001.
Sponsorship: Supported by NIH Award RO1DK49381, the UNC CFAR, P30-HD37260, the Verne R. Caviness General Clinical Research Center RR00046, #DK/AI157810, Swiss National Science Foundation 233-048902.96.
Requests for reprints to: Myron S. Cohen, Department of Medicine, 3003 Old Clinic Bldg. CB7005, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7005, USA.
Objective: To develop a model to predict transmission of HIV-1 from men to women.
Design: HIV-1 in seminal plasma, and endocervical CCR5 receptors were correlated with epidemiological studies of HIV-1 transmission to develop a probabilistic model.
Settings: Semen samples were collected from patient subjects in Seattle Washington, Chapel Hill, North Carolina, and St. Gallen, Switzerland. Endocervical biopsy specimens were obtained from women in Chicago, Illinois.
Participants: Eighty-six men (not receiving antireroviral therapy) in whom CD4 cell count and semen volume were available, and 24 women in whom the number of endocervical CCR5 receptors were determined.
Main outcome measures: Prediction of transmission of HIV-1 from men to women per episode of vaginal intercourse based on the absolute burden of HIV (volume × HIV RNA copies/ml seminal plasma).
Results: The model suggests efficient heterosexual transmission of HIV-1 when semen viral burden is high. When semen contains 100 000 copies of non-syncytium-inducing (NSI) HIV RNA the probability of HIV-1 transmission is 1 per 100 episodes of intercourse; conversely, with 1000 copies NSI HIV RNA in semen, transmission probability is 3 per 10 000 episodes of intercourse.
Conclusions: This model links biological and epidemiological data related to heterosexual HIV-1 transmission. The model can be used to estimate transmission of HIV from men with high semen viral burden from inflammation, or reduced burden after antiretroviral therapy. The results offer a biological explanation for the magnitude of the HIV epidemic in places where earlier studies have shown men have high semen viral burden, such as in sub-Saharan Africa. The model can be used to develop and test HIV-1 prevention strategies.
HIV-1 can be transmitted through contaminated blood and blood products, from mother to child, or through sexual contact . The predominant mode of transmission of HIV worldwide is heterosexual intercourse [2–4].
Epidemiological and mathematical models have been developed to estimate the likelihood of HIV-1 transmission during a single episode of sexual intercourse. Such models are confounded by difficulty in collecting appropriate empirical data from discordant couples (when HIV-1 positive and negative people engage in sex) and from limitations in different kinds of estimation. For example, most published estimates of the probability of sexual transmission of HIV-1 have assumed constant infectivity between couples, ignoring the possibility that acquired immunity might reduce the efficiency of transmission .
The probability of per-partner sexual transmission of HIV-1 has been examined in 11 different studies,  whereas the per-sex-act probability of transmission has been reported in 13 studies [7–19]. The probability of transmission of HIV-1 from male to female during an episode of intercourse has been examined in seven of these studies [7,14–19]. Analysis of data from North American and European studies of heterosexual couples provide estimates of per-sex-act HIV-1 transmission of approximately 1 in 1000 (0.001, ranging from 0.0008 to 0.002) , although the magnitude of the HIV-1 epidemic would argue that these estimates might be unreasonably low.
The transmission of HIV-1 is ultimately a biological event, which depends upon the infectiousness of the HIV-1-infected index case  and the susceptibility of the uninfected partner . Infectiousness is likely determined by the concentration of virus in the genital secretions and by the viral phenotype . We [21,22] and others [23,24] have developed assays to measure the concentration of HIV-1 in male genital secretions, the genotype of HIV-1 in male genital secretions,  and the number of receptors for HIV-1 in the endocervix . We have used these data to develop a model of transmission of HIV-1 from the male to female which correlates biological and epidemiological data. The results can be used to understand better the distribution of HIV-1 transmission probabilities, and to develop better HIV-1 prevention strategies. The results demonstrate that the per-contact transmission probability for transmission of HIV-1 from men to women may be considerably greater in many parts of the world than estimated in epidemiological studies.
A probabilistic model was developed to estimate the male-to-female per-contact HIV-1 transmission probability for a known transmitter and receptor cell counts by using the conditional and unconditional probability theory. This type of model has the advantage that empirical data from different, independent sources can be applied.
We assumed that the best predictor of infectiousness of the male partner is the cell-free virus measured in seminal plasma. It is not known whether HIV-1 is transmitted from cell free virus in the seminal plasma, or from cellular HIV-1 . However, in the absence of genital tract inflammation, cell free HIV-1 in seminal plasma reflects the number of HIV-1 infected cells in semen [27,28]. We also assumed that the risk of HIV-1 transmission remains the same for each episode of intercourse with a partnership, although some have argued that exposure leads to some degree of immunity . We also assumed that total non-synctiuminducing (NSI) HIV-1 RNA concentration (x1) and CD4 + CCR5 receptor cells (x2) were represented by a Pearson's type-1 distribution that could be transformed into a Beta distribution (subtracting the minimum value and divided by the range) . Data with highly varied configurations can be modeled with a Beta distribution. It should be noted, however, that isolates other than NSI can be transmitted sexually  and cells expressing other receptors for HIV-1 may prove receptive .
The natural choices to model a discrete response (infected or not-infected) is to use a logistic probability model. When the likelihood of an event is small we can describe the logistic probability as  :EQUATION
Where Pt/x1, x 2 is the conditional probability of HIV-1 transmission given the values of x1 and x2 (see above).
We have to choose the function g (x1, x2) in such a way that if there is no NSI HIV RNA then there will be no transmission, and if there are no receptor cells then there will be no transmission. We evaluated different functions for g (x1, x2) and the following function that satisfies our conditions:EQUATION
To estimate b1 and b2 we can write the unconditional HIV-1 transmission probability pt as:EQUATION
where t = 1, 2;i = 1, 2. . .n1t and j = 1, 2. . .n2EQUATION
Where α s and β s are Beta distribution parameters. After some algebraic manipulation the final equations can be written as follows  :
for t = 1 we have EQUATION
for t = 2 we have EQUATION
The above two equations do not have algebraic solutions for b1 and b2 Therefore, we used the successive approximation method to get an estimate of b1 and b2 Substituting the values of b1 and b2 in (1) we estimate the male-to-female penile–vaginal per-sexual-act HIV-1 transmission probability with a known infectiousness measure for the male partner and a known susceptibility measure for the female partner.
The model uses extensive data from four different study sites (see Results). Semen specimens were collected at the University of North Carolina, University of Washington, and St. Gallen. Endocervical CCR5 receptors were studied at Northwestern University. The methods used for measurement of HIV-1 in seminal plasma [22,24] and CCR5 receptor density  have been reported previously.
Nine studies (eight from the USA and Europe and one from Africa) have reported the concentration of HIV-1 in seminal plasma . The three largest studies were conducted in Chapel Hill (n = 88), [22,34–36], Seattle (n = 165),  and St. Gallen (n = 100) . The data used for the current analysis included additional subjects who were not available for study at the time the cited papers were written. We evaluated the data from these three centers from the inception of the research up to and including July 1999. We considered only samples collected from visits at which the patients were receiving no antiviral therapy (as antiviral therapy may be expected to reduce HIV-1 in semen [5,37]), and for which the seminal HIV-1 RNA count/ml, semen volume, and CD4 cell count were available.
With these limitations, 41 subjects seen in Chapel Hill between July 1994 and February 1996 provided 64 samples (1–5/subject). The total seminal HIV-1 RNA count in one ejaculate ranged from 2000 to 2 790 000 with a mean of 143 455 and a median of 8100. Seventeen subjects from Seattle, with 40 separate visits, were included. The number of samples collected from subjects ranged from one to three between April 1994 and July 1997. The total HIV-1 RNA in semen in one ejaculate ranged from 30 to 39 795 copies with a mean of 2623 copies and a median of 480 copies. Twenty-eight subjects from the Swiss cohort were included: each subject provided only one sample between October 1994 and December 1997. The total HIV-1 RNA in semen in one ejaculate ranged from 200 to 13 935 418 copies with a mean of 971 510 and a median of 2488 copies.
The total number of samples was divided into two groups: in one group were visits at which subjects had CD4 cell counts ≤ 200 × 106/l and in another group were visits at which subjects had CD4 cell counts > 200 × 106/l. A CD4 cell count of 200 was chosen as a cutoff because of a comparable epidemiological study . In the first group 40 samples from 33 different patients were used and in the second group 92 samples from 53 patients subjects were considered (Table 1). In the first group CD4 cell count was in the range 5–189 × 106/l (median, 105 × 106/l) and in the second group CD4 cell count was in the ranged 202–1240 × 106/l (median, 395 × 106/l).
Semen volume per ejaculate ranged from 0.10 ml to 7.30 ml with a mean of 2.56 ml and a median of 2.30 ml and the distribution was similar in two groups. The mean (median) HIV-1 RNA count/ml was 275, 202 (1302). Total seminal HIV-1 RNA count in one ejaculate was calculated by multiplying the HIV-1 RNA count/ml by the total semen volume. The HIV-1 RNA/ejaculate distribution was different in two groups, as expected based on several studies demonstrating increasing HIV-1 in seminal plasma as CD4 cell counts fall [22,34]. The degree of variation in HIV-1 RNA in semen was greater in the CD4 cell count > 200 × 106/l group as compared with the CD4 cell count ≤ 200 × 106/l group (Table 1).
The efficient transmission of HIV-1 requires that the infectious strain utilize very specific receptors [20,26]. Recent data suggest that HIV-1 variants which use CCR5 receptors (NSI isolates) are preferentially sexually transmitted . As the precise number of NSI isolates in a swarm of HIV-1 in semen is unknown we assumed that it is similar to a swarm of HIV-1 in blood. In Centers for Disease Control (CDC) stage IV CII patients studied by Schuitemaker et al. 70% of the swarm was NSI whereas in CDC stage II 100% of the swarm was NSI, and this distribution was used for our calculations.
Observations were correlated because the visits of an individual patient are not independent. The bootstrap resampling process was used to calculate the Beta distribution parameter estimates for two groups. First, one observation was selected randomly from each subject and the minimum value and the range for the set were calculated. Second, all of the selected observations were transformed by subtracting the minimum value and dividing it by the range. From the transformed variable, the Beta distribution parameter estimates of α and β were calculated by using the maximum likelihood method. Third, this process was repeated 1000 times to obtain 1000 Beta distribution parameter estimates of α and β. Finally, the mean of those 1000 estimates of α and β was calculated. The bootstrap resampling for the two groups was carried out independently. The Beta distribution parameter estimates for the CD4 cell count ≤ 200 × 106/l group were α11 = 0.385, β11 = 5.646 and for the CD4 cell count > 200 × 106/l group were α12 = 0.242, β12 = 1.428.
The number of receptors for HIV-1 will also determine the efficiency of transmission. The receptor cell distribution parameter was estimated from studies in which the CD4 + CCR5 cell count/mm2 in the endocervix was actually measured . The mean (median) receptor cell count was 176.0/mm2 (184.8/mm2) with a minimum of 12.6/mm2 and a maximum of 449.4/mm2. The receptor cell values were transformed by subtracting the minimum value of 12.6/mm2 and dividing by the range of 436.8/mm2. By using the scaled data Beta distribution parameter estimates of α2 = 0.769 and β2 = 1.143 were calculated by using maximum likelihood method.
Also used were the unconditional probability estimates from a published paper  in which the male-to-female per-sex-act penile-vaginal HIV-1 transmission probability was estimated to be 0.0006 for the CD4 cell count ≤ 200 × 106/l group and 0.0007 for the CD4 cell count > 200 × 106/l group. All of the values of P1t, P2t,α11, β11,α12, β12, α2, and β2 were placed in equations (2) and (3) and used the successive approximation method with a precision of two decimal places to estimate b1 and b2 (model parameters). Our estimates were b1 = 0.778 and b2 = 0.604. Thus, the final model equation could be written as:EQUATION
Estimates of the efficiency of transmission of HIV-1 have been derived from epidemiological studies and mathematical models. Epidemiological studies [7,14–19] which have included estimates of male to female sexual transmission of HIV-1 are summarized in Table 2. However, the transmission probabilities presented are so low that it becomes difficult to understand the magnitude of the HIV-1 pandemic, especially in developing countries. An alternative approach to explain the epidemic is the development of mathematical models. For example, Jacquez and coworkers have argued that the majority of sexual transmission of HIV-1 occurs during the narrow window of primary infection .
Greatly improved understanding of the biology of sexual transmission of HIV-1  and collection of large numbers of relevant samples provides a unique opportunity to link epidemiological and biological data. We believe that HIV-1 transmission must depend on the concentration of the appropriate HIV-1 variants in the genital secretions,  and availability of permissive cells . Based on the understanding of the biology of sexual transmission and using data collected in several different studies, we have developed a probabilistic model (equation 2). This model predicts very limited transmission of HIV-1 when the concentration of HIV-1 in semen is low (as is commonly the case in developed countries , and in subjects receiving antiretroviral therapy ). Markedly increased efficiency of HIV-1 transmission is expected to occur when the concentration of HIV-1 in semen becomes greater (Figs 1 and 2).
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.
1. Royce RA, Seña A, Cates W, Cohen MS. Sexual transmission of HIV-1. N Engl J Med 1997, 336: 1072 –1078.
2. Quinn TC. Global burden of the HIV-1 pandemic. Lancet 1996, 348: 99 –106.
3. Guinan ME, Hardy A. Epidemiology of AIDS in women in the United States, 1981 through 1986. JAMA 1987, 257: 2039 –2042.
4. Joint United Nations Programme on HIV-1/AIDS. The HIV-1/AIDS situation in mid 1996, global and regional highlights. UNAIDS Facts, 1996.
5. Vernazza PL, Eron JJ, Fiscus SA, Cohen MS. Sexual transmission of HIV-1, infectiousness and prevention. AIDS 1999, 13: 155 –166.
6. Mastro TD, Kitayaporn D. HIV-1 Type 1 transmission probabilities, estimates from epidemiological studies. AIDS Res. Hum. Retroviruses 1998, 14: 223 –227.
7. Peterman TA, Stonebumer RL, Allen JR, Jaffe HW, Curran JW. Risk of human immunodeficiency virus transmission from heterosexual adults with transfusion-associated infections. JAMA 1988, 259: 55 –58.
8. Fischl MA, Dickinson GM, Scott GB, Klimas N, Fletcher MA, Parks W. Evaluation of heterosexual partners, children, and household contacts of adults with AIDS. JAMA 1987, 257: 640 –644.
9. Longini IM Jr., Clark WS, Haber M, Horsburgh CR. The stages of HIV-1 infection, waiting times and infection transmission probabilities. In Lecture Notes in Biomathematics, Vol. 83, Mathematical and Statistical Approaches to AIDS Epidemiology. Edited by Castillo-Chavez, C. Berlin: Springer-Verlag; 1989: 111 –136.
10. Cameron DW, Simonsen JN, D'Costa LJ. et al. Female to male transmission of human immunodeficiency virus type 1: risk factors for seroconversion in men. Lancet 1989, 2: 403 –407.
11. DeGruttola V, Seage GR, Maver KH, Horsburgh CRJ. Infectiousness of HIV-1 between male homosexual partners. J Clin Epidemiol 1989, 42: 849 –856.
12. Mastro TD, Satten GA, Nopkesom T, Sangkharomya S, Longini IM Jr. Probability of female-to-male transmission of HIV-1 in Thailand. Lancet 1994, 343: 204 –207.
13. Satten GA, Mastro TD, Longini IM Jr. Modelling the female-to-male per-act HIV-1 transmission probability in an emerging epidemic in Asia. Stat Med 1994, 13: 2097 –2106.
14. Padian N, Marquis L, Francis DP. et al. Male-to-female transmission of human immunodeficiency virus. JAMA 1987, 258: 788 –790.
15. Wiley JA, Herschkorn SJ, Padian NS. Heterogeneity in the probability of HIV-1 transmission per sexual contact: the case of male-to-female transmission in penile-vaginal intercourse. Stat Med 1989, 8: 93 –102.
16. Duerr A, Xia Z, Nagachinta T, Tovanabutra S, Tansuhaj A, Nelson K . Probability of male-to-female HIV-1 transmission among married couples in Chiang Mai, Thailand. Tenth International Conference on AIDS. Yokohama, August 1994 [abstract 105C].
17. Downs MA, deVincenzi I. Probability of heterosexual transmission of HIV-1: relationship to the number of unprotected sexual contacts. J Acquir Immune Defic Syndr Hum Retrovirol 1996, 11: 388 –395.
18. Leynaert B, Downs AM, deVincenzi I. Heterosexual transmission of human immunodeficiency virus: variability of infectivity throughout the course of infection. Am J Epidemiol 1998, 148: 88 –96.
19. Shiboski SC, Padian NS. Epidemiological evidence for time variation in HIV-1 infectivity. J Acquir Immune Defic Syndr Hum Retrovirol 1998, 19: 527 –535.
20. Buchacz KA, Wilkinson DA, Krowka JF, Koup RA, Padian NS. Genetic and immunological host factors associated with susceptibility to HIV-1 infection. AIDS 1998, 12: S87 –S94.
21. Dyer JR, Gilliam BL, Eron JJ Jr, Grosso L, Cohen MS, Fiscus SA. Quantitation of human immunodeficiency virus type 1 RNA in cell free seminal plasma: comparison of NASBA with Amplicor reverse transcription-PCR amplification and correlation with quantitative culture. J Virol Methods 1996, 60: 161 –170.
22. Vernazza PL, Gilliam BL, Dyer J. et al. Quantitation of HIV-1 in semen: Correlation with antiviral treatment and immune status. AIDS 1997, 11: 987 –993.
23. Gupta P, Mellors J, Kingsley L. et al. High viral load in semen of human immunodeficiency virus type 1-infected men at all stages of disease and its reduction by therapy with protease and nonnucleoside reverse transcriptase inhibitors. J Virol 1997, 71: 6271 -6275.
24. Coombs RW, Speck CE, Hughes JP. et al. Association between culturable human immunodeficiency virus type 1 (HIV-1-1) in semen and HIV-1 RNA levels in semen and blood: evidence for compartmentalization of HIV-1 between semen and blood. J Infect Dis 1998, 177: 320 –330.
25. Eron JJ, Vernazza PL, Johnston DM. et al. Resistance of HIV-1 to antiretroviral agents in blood and seminal plasma: implications for transmission. AIDS 1998, 12: F181 –F189.
26. Patterson BK, Landay A, Anderson DJ. et al. Repertoire of chemokine receptor expression in the female genital tract, implication for human immunodeficiency virus transmission. Am J Pathol 1998, 153: 481 –490.
27. Speck CE, Coombs RW, Koutsky LA. et al. Risk factors for HIV-1 shedding in semen. Am J Epidemiol 1999, 150: 622 –631.
28. Xu C, Politch JA, Tucker L. et al. Factors associated with increased levels of human immunodeficiency virus type 1 DNA in semen. J Infect Dis 1998, 176: 941 –947.
29. Padian NS, Shiboski SC, Jewell NP. The effect of number of exposure on the risk of heterosexual HIV-1 transmission. J Infect Dis 1990, 161: 833 –877.
30. Elderton WP, Johnson NL. Systems of Frequency cUrves. Cambridge: Cambridge University Press; 1969.
31. Fiore JR, Bjorndal A, Peipke KA. et al. The biological phenotype of HIV-1 is usually retained during and after sexual transmission. Virology 1994, 204: 297 –303.
32. Littman DR. Chemokine receptors, keys to AIDS pathogenesis? Cell 1998, 93: 677 –680.
33. Chakraborty H, Sen Pk, Helms RW, Cohen MS. Probabilistic model to estimate male-to-female sexual transmission of HIV-1. Symposium on Statistical Methods, CDC and ATSDR, Atlanta, January 2001 [abstract 5].
34. Dyer JR, Eron JJ, Hoffman IF. et al. Association of CD4 cell depletion and elevated blood and seminal plasma human immunodeficiency virus type 1 (HIV-1) RNA concentrations with genital ulcer disease in HIV-1-infected men in Malawi. J Infect Dis 1998, 177: 224 –227.
35. Gilliam B, Dyer JR, Fiscus SA. et al. Effects of reverse transcriptase inhibitor therapy on the HIV-1 viral burden in semen. J Acquir Immune Defic Syndr Hum Retrovirol 1997, 15: 54 –60.
36. Dyer JR, Kazembe P, Vernazza PL. et al. High levels of human immunodeficiency virus type 1 in blood and semen of seropositive men in sub-Saharan Africa. J Infect Dis 1998, 177: 1742 –1746.
37. Kashuba ADM, Dyer JR, Kramer LM, Raasch RH, Eron JJ, Cohen MS. Antiretroviral-drug concentrations in semen: implications for sexual transmission of human immunodeficiency virus type 1. Antimicrob Agents Chemother 1999, 43: 1817 –1826.
38. Littman DR. Chemokine Receptors, keys to AIDS Pathogenesis? Cell 1998, 93: 677 –680.
39. Schuitemaker H, Koot M, Kootstra NA. et al. Biological phenotype of human immunodeficiency virus type 1 is associated with a shift from monocytotropic to T-cell-topic virus population. J Virol 1992, 66: 1345 –1360.
40. Vernazza PL, Eron JJ, Cohen MS, van der Horst CM, Troiani L, Fiscus SA. Detection and biologic characterization of infectious HIV-1 in semen of seropositive men. AIDS 1994, 8: 1325 –1329.
41. Jacquez JA, Koopman JS, Simon CP, Longini IM. Role of the primary infection in epidemics of HIV-1 infection in gay cohorts. J Acquir Immune Def Syndr 1994, 7: 1169 –1184.
42. Koot M, Keet ID, Vos AH. et al. Prognostic value of HIV-1 syncytium-inducing phenotype for rate of CD4+ cell depletion and progression to AIDS. Ann Intern Med. 1993, 118: 681 –688.
43. Bozzette SA, McCutchan JA, Spector SA, Wright B, Richman DD. A cross-sectional comparison of persons with syncytium- and non-syncytium-inducing human immunodeficiency virus. J Infect Dis 1993, 168: 1374 –1379.
44. Fiscus SA, Branbilla D, Coombs RW. et al. Multi-center evaluation of methods to quantitate human immunodeficiency virus type 1 RNA in seminal plasma. J Clin Microbiol, 2000, 38: 2348 –2353.
45. Quinn TC, Wawer MJ, Sewankambo N. et al. Viral load and the risk of heterosexual transmission of human immunodeficiency virus type 1. N Engl J Med 2000, 342: 921 –929.
46. Chakraborty H, Helms RW, Cohen MS. Estimating correlation by using General Linear Mixed Models in different settings: correlation between the concentration of blood HIV-1 RNA and semen HIV-1 RNA. The International Biometric Society/Eastern North American Region (ENAR) Conference. Atlanta, March–April 1999.
47. Wawer MJ, Sewankambo NK, Serwadda D. et al. Control of sexually transmitted diseases for AIDS prevention in Uganda: a randomized community trial. Lancet 1999, 353: 525 –535.
48. Cohen MS, Hoffman IF, Royce RA. et al. Reduction of concentration of HIV-1-1-1 in semen after treatment of urethritis: implications for prevention of sexual transmission of HIV-1. Lancet 1997, 349: 1868 –1873.
49. Blower SM, Gershengorn HB, Grant RM. A tale of two futures: HIV-1 and antiretroviral therapy in San Francisco. Science 2000, 287: 650 –654.
50. Cohen MS. Preventing sexual transmission of HIV–New lessons from sub-Saharan Africa. New Engl. J. Med 2000, 342: 970 –972.
This article has been cited 137 time(s).
Journal of Clinical VirologyAnalysis of HIV-1 viral load in seminal plasma samplesJournal of Clinical Virology
Journal of VirologyRepeated low-dose mucosal simian immunodeficiency virus SIVmac239 challenge results in the same viral and immunological kinetics as high-dose challenge: a model for the evaluation of vaccine efficacy in nonhuman primatesJournal of Virology
Sexually Transmitted InfectionsThe effects of urethritis on seminal plasma HIV-1 RNA loads in homosexual men not receiving antiretroviral therapySexually Transmitted Infections
Current Opinion in Investigational Drugs
Microbicides for multidrug-resistant and multitropic HIV-1
Current Opinion in Investigational Drugs, 9(2):
Clinical Infectious DiseasesInfection control in jails and prisonsClinical Infectious Diseases
CellSemen-derived amyloid fibrils drastically enhance HIV infectionCell
Journal of Infectious DiseasesHIV-1 transmission, by stage of infectionJournal of Infectious Diseases
International Journal of Std & AIDSDenialism undermines AIDS prevention in sub-Saharan AfricaInternational Journal of Std & AIDS
VaccineUse of predictive markers of HIV disease progression in vaccine trialsVaccine
AIDS Research and Human Retroviruses
Importance of Antiretroviral drug concentrations in sanctuary sites and viral reservoirs
AIDS Research and Human Retroviruses, 19(3):
Scandinavian Journal of Infectious DiseasesThe legal proceeding: Introduction of the witnessesScandinavian Journal of Infectious Diseases
Journal of Clinical MicrobiologyUse of Sno Strip filter-paper wicks for collection of genital-tract samples allows reproducible determination of human immunodeficiency virus type I (HIV-1) RNA viral load with a commercial HIV-1 viral load assayJournal of Clinical Microbiology
International Journal of Std & AIDS
Fatal attraction: sex, sexually transmitted infections and HIV-1
International Journal of Std & AIDS, 17():
Journal of VirologyVaccine-induced cellular immune responses reduce plasma viral concentrations after repeated low-dose challenge with pathogenic simian immunodeficiency virus SIVmac239Journal of Virology
VirologyHIV-1 DNA/MVA vaccination reduces the per exposure probability of infection during repeated mucosal SHIV challengesVirology
Reproductive options for HIV-serodiscordant couples
AIDS Reviews, 8(3):
AIDS Research and Human RetrovirusesBacterial vaginosis, not HIV, is primarily responsible for increased vaginal concentrations of proinflammatory cytokinesAIDS Research and Human Retroviruses
AIDS Research and Human RetrovirusesHIV Dynamics in Seminal Plasma during Primary HIV InfectionAIDS Research and Human Retroviruses
Journal of Law Medicine & Ethics
HIV and the law: Integrating law, policy, and social epidemiology
Journal of Law Medicine & Ethics, 30(4):
Retroviruses of Human AIDS and Related Animal Diseases
Vaginal application of anti-gp120 monoclonal antibody b12 prevents SHIV-162P vaginal transmission to macaques
Retroviruses of Human AIDS and Related Animal Diseases, ():
HIV superinfection: clinical and biological implications
Medicina Clinica, 121(5):
Sexually Transmitted DiseasesChanges in the transmission dynamics of the HIV epidemic after the wide-scale use of antiretroviral therapy could explain increases in sexually transmitted infections - Results from mathematical modelsSexually Transmitted Diseases
Journal of VirologyInteractions between natural killer cells and antibody Fc result in enhanced antibody neutralization of human immunodeficiency virus type 1Journal of Virology
Human ReproductionIn vitro testing of rationally designed spermicides for selectively targeting human sperm in vagina to ensure safe contraception daggerHuman Reproduction
Clinical Infectious Diseases
Recommendations for incorporating human immunodeficiency virus (HIV) prevention into the medical care of persons living with HIV
Clinical Infectious Diseases, 38(1):
AddictionThe cost-effectiveness of HIV preventive measures among injecting drug users in Svetlogorsk, BelarusAddiction
Journal of Clinical InvestigationThe spread, treatment, and prevention of HIV-1: evolution of a global pandemicJournal of Clinical Investigation
Sexually transmitted infections: impact on male fertility
Current Hiv Research
Relationship between HIV-RNA load in blood and semen in antiretroviral-naive and experienced men and effect of asymptomatic sexually transmissible infections
Current Hiv Research, 6(2):
AIDS Care-Psychological and Socio-Medical Aspects of AIDS/HivDiscussion and revision of the mathematical modeling tool described in the previously published article "Modeling HIV Transmission risk among Mozambicans prior to their initiating highly active antiretroviral therapy"AIDS Care-Psychological and Socio-Medical Aspects of AIDS/Hiv
AIDS and BehaviorMental Health Treatment to Reduce HIV Transmission Risk Behavior: A Positive Prevention ModelAIDS and Behavior
Rapid dissemination of SIV following oral inoculation
Jaids-Journal of Acquired Immune Deficiency Syndromes
Topic II: Hormonal influences on HIV acquisition - Hormonal upregulation of CCR5 expression on T lymphocytes as a possible mechanism for increased HIV-1 risk
Jaids-Journal of Acquired Immune Deficiency Syndromes, 38():
How many sexually-acquired HIV infections in the USA are due to acute-phase HIV transmission?
Theoretical Population BiologyEvaluating the importance of within- and between-host selection pressures on the evolution of chronic pathogensTheoretical Population Biology
Mathematical BiosciencesThe probability of HIV infection in a new host and its reduction with microbicidesMathematical Biosciences
Medicina ClinicaHIV sexual transmission. Should we review the risk among individuals with long-term viral supression?Medicina Clinica
International Family Planning Perspectives
Protecting young women from HIV/AIDS: The case against child and adolescent marriage
International Family Planning Perspectives, 32(2):
AIDS Care-Psychological and Socio-Medical Aspects of AIDS/HivModeling HIV transmission risk among Mozambicans prior to their initiating highly active antiretroviral therapyAIDS Care-Psychological and Socio-Medical Aspects of AIDS/Hiv
Nature Reviews MicrobiologyMucosal delivery of therapeutic and prophylactic molecules using lactic acid bacteriaNature Reviews Microbiology
Lancet Infectious Diseases
Vaginal microbicides and the prevention of HIV transmission
Lancet Infectious Diseases, 8():
Journal of Infectious Diseases
The pharmacokinetics of amprenavir, zidovudine, and lamivudine in the genital tracts of men infected with human immunodeficiency virus type 1 (AIDS Clinical Trials Group Study 850)
Journal of Infectious Diseases, 186(2):
Statistics in MedicineEstimating correlation by using a general linear mixed model: evaluation of the relationship between the concentration of HIV-1 RNA in blood and semenStatistics in Medicine
Journal of Infectious Diseases
Higher concentration of HIV RNA in rectal mucosa secretions than in blood and seminal plasma, among men who have sex with men, independent of antiretroviral therapy
Journal of Infectious Diseases, 190(1):
Journal of VirologySemen-specific genetic characteristics of human immunodeficiency virus type 1 envJournal of Virology
International Journal of AndrologyHIV infection of the male genital tract - consequences for sexual transmission and reproductionInternational Journal of Andrology
Bmc Infectious DiseasesWater dispersible microbicidal cellulose acetate phthalate filmBmc Infectious Diseases
Journal of Medical Ethics
Use of assisted reproductive technology to reduce the risk of transmission of HIV in discordant couples wishing to have their own children where the male partner is seropositive with an undetectable viral load
Journal of Medical Ethics, 29(6):
Journal of Infectious Diseases
Brief but efficient: Acute HIV infection and the sexual transmission of HIV
Journal of Infectious Diseases, 189():
Journal of Infectious Diseases
Potential effect of HIV type 1 antiretroviral and herpes simplex virus type 2 antiviral therapy on transmission and acquisition of HIV type 1 infection
Journal of Infectious Diseases, 191():
Journal of Pharmaceutical SciencesTemperature and pH sensitive hydrogels: An approach towards smart semen-triggered vaginal microbicidal vehiclesJournal of Pharmaceutical Sciences
Nature MedicinePrevention of virus transmission to macaque monkeys by a vaginally applied monoclonal antibody to HIV-1 gp120Nature Medicine
Proceedings of the National Academy of Sciences of the United States of AmericaInhibition of HIV infectivity by a natural human isolate of Lactobacillus jensenii engineered to express functional two-domain CD4Proceedings of the National Academy of Sciences of the United States of America
Journal of Infectious Diseases
Amplified HIV transmission and new approaches to HIV prevention
Journal of Infectious Diseases, 191(9):
Molecular TherapyReplication-competent vectors and empty virus-like particles: New retroviral vector designs for cancer gene therapy or vaccinesMolecular Therapy
New England Journal of Medicine
Current concepts: An HIV vaccine - Evolving concepts
New England Journal of Medicine, 356():
Swiss Medical Weekly
Unusually high HIV infectiousness in an HIV-, HCV- and HSV-2-coinfected heterosexual man
Swiss Medical Weekly, 139():
Sexually Transmitted Diseases
The epidemiological and control implications of HIV transmission probabilities within partnerships
Sexually Transmitted Diseases, 29():
Journal of the National Medical Association
Hiv/aids prevention in Latino and African-American communities
Journal of the National Medical Association, 96(2):
Sexually Transmitted InfectionsModelling the cost effectiveness of rapid point of care diagnostic tests for the control of HIV and other sexually transmitted infections among female sex workersSexually Transmitted Infections
Canadian Journal of Public Health-Revue Canadienne De Sante Publique
Understanding HIV viral load - Implications for counselling
Canadian Journal of Public Health-Revue Canadienne De Sante Publique, 99(3):
Applied and Environmental MicrobiologyEngineering of a human vaginal Lactobacillus strain for surface expression of two-domain CD4 moleculesApplied and Environmental Microbiology
American Journal of Obstetrics and GynecologyGenital tract and plasma human immunodeficiency virus viral load throughout the menstrual cycle in women who are infected with ovulatory human immunodeficiency virusAmerican Journal of Obstetrics and Gynecology
Journal of Clinical InvestigationAcute HIV revisited: new opportunities for treatment and preventionJournal of Clinical Investigation
VaccineA review of vaccine research and development: The human immunodeficiency virus (HIV)Vaccine
Statistics in MedicineBivariate random effect model using skew-normal distribution with application to HIV-RNAStatistics in Medicine
Current Hiv Research
HIV-1-discordant couples in sub-Saharan Africa: Explanations and implications for high rates of discordancy
Current Hiv Research, 5(4):
Bmc Public HealthModelling the impact and cost-effectiveness of the HIV intervention programme amongst commercial sex workers in Ahmedabad, Gujarat, IndiaBmc Public Health
Journal of Clinical MicrobiologyDetermining Seminal Plasma Human Immunodeficiency Virus Type 1 Load in the Context of Efficient Highly Active Antiretroviral TherapyJournal of Clinical Microbiology
Human ReproductionAssisted procreation in cases of hepatitis B, hepatitis C or human immunodeficiency virus infection of the male partnerHuman Reproduction
Plos MedicineWhich topical microbicides for blocking HIV-1 transmission will work in the real world?Plos Medicine
AddictionCould the CARE-SHAKTI intervention for injecting drug users be maintaining the low HIV prevalence in Dhaka, Bangladesh?Addiction
Is transmission of HIV-1 in non-viraemic serodiscordant couples possible?
Antiviral Therapy, 13(5):
Journal of VirologyT-Cell Vaccination Reduces Simian Immunodeficiency Virus Levels in SemenJournal of Virology
Biophysical JournalTransport Theory for HIV Diffusion through In Vivo Distributions of Topical Microbicide GelsBiophysical Journal
Lancet Infectious Diseases
Heterosexual risk of HIV-1 infection per sexual act: systematic review and meta-analysis of observational studies
Lancet Infectious Diseases, 9(2):
Journal of VirologyMultispecific vaccine-induced mucosal cytotoxic T lymphocytes reduce acute-phase viral replication but fail in long-term control of simian immunodeficiency virus SIVmac239Journal of Virology
Current Hiv Research
Pathophysiology of HIV-1 in semen: Current evidence for compartmentalisation and penetration by antiretroviral drugs
Current Hiv Research, 3(3):
Current Pharmaceutical Design
Clinical development of microbicides for the prevention of HIV infection
Current Pharmaceutical Design, 10(3):
Nature Reviews MicrobiologyThe role of sexually transmitted diseases in HIV transmissionNature Reviews Microbiology
Theoretical Population BiologyEvolution of virulence: Interdependence, constraints, and selection using nested modelsTheoretical Population Biology
Nature MedicineAntiretroviral treatment for HIV infection in developing countries: an attainable new paradigmNature Medicine
Journal of Infectious Diseases
Questioning Wawer et al.'s estimated rate of sexual HIV transmission from persons with early HIV infections - Reply to Gisselquist and Potterat
Journal of Infectious Diseases, 192(8):
American Journal of EpidemiologyModeling the sexual transmissibility of human papillomavirus infection using stochastic computer simulation and empirical data from a cohort study of young women in Montreal, CanadaAmerican Journal of Epidemiology
Bmc Infectious DiseasesVaginal microbicides: detecting toxicities in vivo that paradoxically increase pathogen transmissionBmc Infectious Diseases
AIDS vaccine development and challenge viruses: Getting real
Annals of Internal Medicine
Narrative review: Antiretroviral therapy to prevent the sexual transmission of HIV-1
Annals of Internal Medicine, 146(8):
Plos MedicineEpisodic sexual transmission of HIV revealed by molecular phylodynamicsPlos Medicine
Nature MedicineEffective, low-titer antibody protection against low-dose repeated mucosal SHIV challenge in macaquesNature Medicine
AntibiotiquesPlace of vaginal microbicides in the prevention of infection by human immunodeficiency virusAntibiotiques
Journal of Medical VirologyAnalysis of HIV-1 variation in blood and semen during treatment and treatment interruptionJournal of Medical Virology
Bmc Infectious DiseasesAnti-HIV-1 activity of anionic polymers: a comparative study of candidate microbicidesBmc Infectious Diseases
International Journal of Std & AIDS
International Journal of Std & AIDS, 13():
Journal of VirologyMultiple V1/V2 env variants are frequently present during primary infection with human immunodeficiency virus typeJournal of Virology
Infections in Medicine
Sexual transmission of HIV-1: Preexposure and postexposure prophylaxis
Infections in Medicine, 22(4):
Current Hiv Research
Factors affecting sexual transmission of HIV-1: Current evidence and implications for prevention
Current Hiv Research, 3(3):
AIDS and BehaviorSocial discrimination, concurrent sexual partnerships, and HIV risk among men who have sex with men in Shanghai, ChinaAIDS and Behavior
Hiv MedicineBritish HIV Association, BASHH and FSRH guidelines for the management of the sexual and reproductive health of people living with HIV infection 2008Hiv Medicine
Immunology and Allergy Clinics of North AmericaUse of assisted reproductive technology to prevent the transmission of HIV-1 in HIV-discordant couples desiring childrenImmunology and Allergy Clinics of North America
Genital shedding of HIV-1 despite successful antiretroviral therapy
Journal of Infectious Diseases
Human genital epithelial cells capture cell-free human immunodeficiency virus type 1 and transmit the virus to CD4(+) cells: Implications for mechanisms of sexual transmission
Journal of Infectious Diseases, 188():
Scandinavian Journal of Infectious DiseasesBrief summary of the legal proceedingScandinavian Journal of Infectious Diseases
Human Reproduction UpdateReproductive assistance in HIV serodiscordant couplesHuman Reproduction Update
Proceedings of the National Academy of Sciences of the United States of AmericaIntravaginal ring eluting tenofovir disoproxil fumarate completely protects macaques from multiple vaginal simian-HIV challengesProceedings of the National Academy of Sciences of the United States of America
Current Opinion in Obstetrics and GynecologySperm washing, use of HAART and role of elective Caesarean sectionCurrent Opinion in Obstetrics and Gynecology
JAIDS Journal of Acquired Immune Deficiency SyndromesThe Pharmacokinetics and Viral Activity of Tenofovir in the Male Genital TractJAIDS Journal of Acquired Immune Deficiency Syndromes
JAIDS Journal of Acquired Immune Deficiency SyndromesLower Genitourinary Tract Sources of Seminal HIVJAIDS Journal of Acquired Immune Deficiency Syndromes
JAIDS Journal of Acquired Immune Deficiency SyndromesDifferential Extracellular and Intracellular Concentrations of Zidovudine and Lamivudine in Semen and Plasma of HIV-1-Infected MenJAIDS Journal of Acquired Immune Deficiency Syndromes
JAIDS Journal of Acquired Immune Deficiency SyndromesMaraviroc Concentrates in the Cervicovaginal Fluid and Vaginal Tissue of HIV-Negative WomenJAIDS Journal of Acquired Immune Deficiency Syndromes
JAIDS Journal of Acquired Immune Deficiency SyndromesThe Cost-Effectiveness of Treating Male Trichomoniasis to Avert HIV Transmission in Men Seeking Sexually Transmitted Disease Care in MalawiJAIDS Journal of Acquired Immune Deficiency Syndromes
Sexually Transmitted DiseasesWhen People With HIV Get Syphilis: Triple JeopardySexually Transmitted Diseases
Sexually Transmitted DiseasesThe Algebra of Condoms and AbstinenceSexually Transmitted Diseases
Sexually Transmitted DiseasesThomas Parran Award Lecture: Transmission and Prevention of Transmission of HIV-1Sexually Transmitted Diseases
Sexually Transmitted DiseasesSTD Treatment: How Can It Improve HIV Prevention in the South?Sexually Transmitted Diseases
HIV-1; transmission; semen; heterosexual
© 2001 Lippincott Williams & Wilkins, Inc.
Highlight selected keywords in the article text.