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Antiretroviral pre-exposure prophylaxis prevents vaginal transmission of HIV-1 in humanized BLT mice.

Denton PW, Estes JD, Sun Z, Othieno FA, Wei BL, Wege AK, Powell DA, Payne D, Haase AT, Garcia JV - PLoS Med. (2008)

Bottom Line: Effects of HIV-1 infection include CD4+ T cell depletion in gut-associated lymphoid tissue (GALT) that closely mimics what is observed in HIV-1-infected humans.We also show that pre-exposure prophylaxis with antiretroviral drugs is a highly effective method for preventing vaginal HIV-1 transmission.Whereas 88% (7/8) of BLT mice inoculated vaginally with HIV-1 became infected, none of the animals (0/5) given pre-exposure prophylaxis of emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) showed evidence of infection (Chi square = 7.5, df = 1, p = 0.006).

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Division of Infectious Diseases, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States of America.

ABSTRACT

Background: Worldwide, vaginal transmission now accounts for more than half of newly acquired HIV-1 infections. Despite the urgency to develop and implement novel approaches capable of preventing HIV transmission, this process has been hindered by the lack of adequate small animal models for preclinical efficacy and safety testing. Given the importance of this route of transmission, we investigated the susceptibility of humanized mice to intravaginal HIV-1 infection.

Methods and findings: We show that the female reproductive tract of humanized bone marrow-liver-thymus (BLT) mice is reconstituted with human CD4+ T and other relevant human cells, rendering these humanized mice susceptible to intravaginal infection by HIV-1. Effects of HIV-1 infection include CD4+ T cell depletion in gut-associated lymphoid tissue (GALT) that closely mimics what is observed in HIV-1-infected humans. We also show that pre-exposure prophylaxis with antiretroviral drugs is a highly effective method for preventing vaginal HIV-1 transmission. Whereas 88% (7/8) of BLT mice inoculated vaginally with HIV-1 became infected, none of the animals (0/5) given pre-exposure prophylaxis of emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) showed evidence of infection (Chi square = 7.5, df = 1, p = 0.006).

Conclusions: The fact that humanized BLT mice are susceptible to intravaginal infection makes this system an excellent candidate for preclinical evaluation of both microbicides and pre-exposure prophylactic regimens. The utility of humanized mice to study intravaginal HIV-1 transmission is particularly highlighted by the demonstration that pre-exposure prophylaxis can prevent intravaginal HIV-1 transmission in the BLT mouse model.

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Related in: MedlinePlus

Systemic CD4+ T Cell Loss Resulting from Intravaginal HIV-1 Infection in Humanized BLT Mice(A) Comparison of the levels of CD4+ or CD8+ human T cells in the indicated tissues in representative BLT mice that were either naive, HIV-1 infected, or that received FTC/TDF for pre-exposure prophylaxis prior to exposure to HIV-1. Note the HIV-1 induced reduction in the double-positive CD4+CD8+ thymocytes.(B and C) Box plots depicting the levels of CD4+ (B) or CD8+ (C) T cells in the indicated tissues for naive (green), HIV-1 infected (white), and FTC/TDF-treated plus HIV-1–exposed (red) BLT mice. In these plots, the boxes extend from the first to the third quartiles, enclosing the middle 50% of the data. The middle line within each box indicates the median of the data, whereas the vertical line extends from lowest to the highest values. Data from naive, HIV-1-, or FTC/TDF-treated plus HIV-1–exposed mice were not collected on the same day. Naive (n = 5), HIV-1 infected (n = 4), and FTC/TDF + HIV-1 (n = 3). Flow cytometry gating for this figure was performed as described for Figure 2.BM, bone marrow; LN, lymph node; PB, peripheral blood; Thymic Org., implanted thymic organoid.
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pmed-0050016-g003: Systemic CD4+ T Cell Loss Resulting from Intravaginal HIV-1 Infection in Humanized BLT Mice(A) Comparison of the levels of CD4+ or CD8+ human T cells in the indicated tissues in representative BLT mice that were either naive, HIV-1 infected, or that received FTC/TDF for pre-exposure prophylaxis prior to exposure to HIV-1. Note the HIV-1 induced reduction in the double-positive CD4+CD8+ thymocytes.(B and C) Box plots depicting the levels of CD4+ (B) or CD8+ (C) T cells in the indicated tissues for naive (green), HIV-1 infected (white), and FTC/TDF-treated plus HIV-1–exposed (red) BLT mice. In these plots, the boxes extend from the first to the third quartiles, enclosing the middle 50% of the data. The middle line within each box indicates the median of the data, whereas the vertical line extends from lowest to the highest values. Data from naive, HIV-1-, or FTC/TDF-treated plus HIV-1–exposed mice were not collected on the same day. Naive (n = 5), HIV-1 infected (n = 4), and FTC/TDF + HIV-1 (n = 3). Flow cytometry gating for this figure was performed as described for Figure 2.BM, bone marrow; LN, lymph node; PB, peripheral blood; Thymic Org., implanted thymic organoid.

Mentions: The systemic effects of HIV-1 infection in humans are inherently difficult to study. Therefore, we took advantage of the systemic repopulation of BLT mice with human lymphocytes to evaluate the effects of HIV-1 infection in relevant internal organs. Since CD4+ T cell depletion is a hallmark of HIV-1 infection, we compared the levels of these cells throughout the body of naive versus HIV-1–infected versus pre-exposure FTC/TDF-treated BLT mice. No statistical difference was observed when CD4+ T cell levels of all tissues combined in naive and pre-exposure FTC/TDF-treated BLT mice were compared (% Mean1 − % Mean2 [M1 − M2] = 1.2 ± 8.8, t = 0.13, df = 65, p = 0.90). However, when comparing HIV-1–infected versus FTC/TDF-treated and HIV-1–exposed mice, statistically significant reductions in CD4+ T cells were noted in peripheral blood (M1 − M2 = −49 ± 13, t = 3.8, df = 5, p = 0.012), bone marrow (M1 − M2 = −52 ± 4.1, t = 13, df = 5, p < 0.001), spleen (M1 − M2 = −36 ± 4.7, t = 7.5, df = 5, p < 0.001), lymph nodes (M1 − M2 = −28 ± 7.4, t = 3.7, df = 5, p = 0.013), liver (M1 − M2 = −34 ± 11, t = 3.2, df = 5, p = 0.024), and lung (M1 − M2 = −45 ± 8.1, t = 5.6, df = 5, p = 0.003) in HIV-1–infected mice; no significant difference was noted in the thymic organoid (M1 − M2 = 1.8 ± 4.5, t = 0.40, df = 5, p = 0.70) (Figure 3A and 3B). Together with the reduction in the levels of CD4+ human T cells, there was a concomitant statistically significant increase in the levels of CD8+ human T cells comparing HIV-1–infected versus FTC/TDF-treated and HIV-1–exposed mice in all tissues tested, including peripheral blood (M1 − M2 = 45 ± 13, t = 3.4, df = 5, p = 0.019), bone marrow (M1 − M2 = 46 ± 3.5, t = 13, df = 5, p < 0.001), thymic organoid (M1 − M2 = 26 ± 9.9, t = 2.7, df = 5, p = 0.045), spleen (M1 − M2 = 29 ± 2.8, t = 10, df = 5, p < 0.001), lymph nodes (M1 − M2 = 27 ± 7.8, t = 3.4, df = 5, p = 0.019), liver (M1 − M2 = 34 ± 10, t = 3.4, df = 5, p = 0.019), and lung (M1 − M2 = 40 ± 6.5, t = 6.2, df = 5, p = 0.002) (Figure 3A and 3C).


Antiretroviral pre-exposure prophylaxis prevents vaginal transmission of HIV-1 in humanized BLT mice.

Denton PW, Estes JD, Sun Z, Othieno FA, Wei BL, Wege AK, Powell DA, Payne D, Haase AT, Garcia JV - PLoS Med. (2008)

Systemic CD4+ T Cell Loss Resulting from Intravaginal HIV-1 Infection in Humanized BLT Mice(A) Comparison of the levels of CD4+ or CD8+ human T cells in the indicated tissues in representative BLT mice that were either naive, HIV-1 infected, or that received FTC/TDF for pre-exposure prophylaxis prior to exposure to HIV-1. Note the HIV-1 induced reduction in the double-positive CD4+CD8+ thymocytes.(B and C) Box plots depicting the levels of CD4+ (B) or CD8+ (C) T cells in the indicated tissues for naive (green), HIV-1 infected (white), and FTC/TDF-treated plus HIV-1–exposed (red) BLT mice. In these plots, the boxes extend from the first to the third quartiles, enclosing the middle 50% of the data. The middle line within each box indicates the median of the data, whereas the vertical line extends from lowest to the highest values. Data from naive, HIV-1-, or FTC/TDF-treated plus HIV-1–exposed mice were not collected on the same day. Naive (n = 5), HIV-1 infected (n = 4), and FTC/TDF + HIV-1 (n = 3). Flow cytometry gating for this figure was performed as described for Figure 2.BM, bone marrow; LN, lymph node; PB, peripheral blood; Thymic Org., implanted thymic organoid.
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pmed-0050016-g003: Systemic CD4+ T Cell Loss Resulting from Intravaginal HIV-1 Infection in Humanized BLT Mice(A) Comparison of the levels of CD4+ or CD8+ human T cells in the indicated tissues in representative BLT mice that were either naive, HIV-1 infected, or that received FTC/TDF for pre-exposure prophylaxis prior to exposure to HIV-1. Note the HIV-1 induced reduction in the double-positive CD4+CD8+ thymocytes.(B and C) Box plots depicting the levels of CD4+ (B) or CD8+ (C) T cells in the indicated tissues for naive (green), HIV-1 infected (white), and FTC/TDF-treated plus HIV-1–exposed (red) BLT mice. In these plots, the boxes extend from the first to the third quartiles, enclosing the middle 50% of the data. The middle line within each box indicates the median of the data, whereas the vertical line extends from lowest to the highest values. Data from naive, HIV-1-, or FTC/TDF-treated plus HIV-1–exposed mice were not collected on the same day. Naive (n = 5), HIV-1 infected (n = 4), and FTC/TDF + HIV-1 (n = 3). Flow cytometry gating for this figure was performed as described for Figure 2.BM, bone marrow; LN, lymph node; PB, peripheral blood; Thymic Org., implanted thymic organoid.
Mentions: The systemic effects of HIV-1 infection in humans are inherently difficult to study. Therefore, we took advantage of the systemic repopulation of BLT mice with human lymphocytes to evaluate the effects of HIV-1 infection in relevant internal organs. Since CD4+ T cell depletion is a hallmark of HIV-1 infection, we compared the levels of these cells throughout the body of naive versus HIV-1–infected versus pre-exposure FTC/TDF-treated BLT mice. No statistical difference was observed when CD4+ T cell levels of all tissues combined in naive and pre-exposure FTC/TDF-treated BLT mice were compared (% Mean1 − % Mean2 [M1 − M2] = 1.2 ± 8.8, t = 0.13, df = 65, p = 0.90). However, when comparing HIV-1–infected versus FTC/TDF-treated and HIV-1–exposed mice, statistically significant reductions in CD4+ T cells were noted in peripheral blood (M1 − M2 = −49 ± 13, t = 3.8, df = 5, p = 0.012), bone marrow (M1 − M2 = −52 ± 4.1, t = 13, df = 5, p < 0.001), spleen (M1 − M2 = −36 ± 4.7, t = 7.5, df = 5, p < 0.001), lymph nodes (M1 − M2 = −28 ± 7.4, t = 3.7, df = 5, p = 0.013), liver (M1 − M2 = −34 ± 11, t = 3.2, df = 5, p = 0.024), and lung (M1 − M2 = −45 ± 8.1, t = 5.6, df = 5, p = 0.003) in HIV-1–infected mice; no significant difference was noted in the thymic organoid (M1 − M2 = 1.8 ± 4.5, t = 0.40, df = 5, p = 0.70) (Figure 3A and 3B). Together with the reduction in the levels of CD4+ human T cells, there was a concomitant statistically significant increase in the levels of CD8+ human T cells comparing HIV-1–infected versus FTC/TDF-treated and HIV-1–exposed mice in all tissues tested, including peripheral blood (M1 − M2 = 45 ± 13, t = 3.4, df = 5, p = 0.019), bone marrow (M1 − M2 = 46 ± 3.5, t = 13, df = 5, p < 0.001), thymic organoid (M1 − M2 = 26 ± 9.9, t = 2.7, df = 5, p = 0.045), spleen (M1 − M2 = 29 ± 2.8, t = 10, df = 5, p < 0.001), lymph nodes (M1 − M2 = 27 ± 7.8, t = 3.4, df = 5, p = 0.019), liver (M1 − M2 = 34 ± 10, t = 3.4, df = 5, p = 0.019), and lung (M1 − M2 = 40 ± 6.5, t = 6.2, df = 5, p = 0.002) (Figure 3A and 3C).

Bottom Line: Effects of HIV-1 infection include CD4+ T cell depletion in gut-associated lymphoid tissue (GALT) that closely mimics what is observed in HIV-1-infected humans.We also show that pre-exposure prophylaxis with antiretroviral drugs is a highly effective method for preventing vaginal HIV-1 transmission.Whereas 88% (7/8) of BLT mice inoculated vaginally with HIV-1 became infected, none of the animals (0/5) given pre-exposure prophylaxis of emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) showed evidence of infection (Chi square = 7.5, df = 1, p = 0.006).

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Division of Infectious Diseases, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States of America.

ABSTRACT

Background: Worldwide, vaginal transmission now accounts for more than half of newly acquired HIV-1 infections. Despite the urgency to develop and implement novel approaches capable of preventing HIV transmission, this process has been hindered by the lack of adequate small animal models for preclinical efficacy and safety testing. Given the importance of this route of transmission, we investigated the susceptibility of humanized mice to intravaginal HIV-1 infection.

Methods and findings: We show that the female reproductive tract of humanized bone marrow-liver-thymus (BLT) mice is reconstituted with human CD4+ T and other relevant human cells, rendering these humanized mice susceptible to intravaginal infection by HIV-1. Effects of HIV-1 infection include CD4+ T cell depletion in gut-associated lymphoid tissue (GALT) that closely mimics what is observed in HIV-1-infected humans. We also show that pre-exposure prophylaxis with antiretroviral drugs is a highly effective method for preventing vaginal HIV-1 transmission. Whereas 88% (7/8) of BLT mice inoculated vaginally with HIV-1 became infected, none of the animals (0/5) given pre-exposure prophylaxis of emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) showed evidence of infection (Chi square = 7.5, df = 1, p = 0.006).

Conclusions: The fact that humanized BLT mice are susceptible to intravaginal infection makes this system an excellent candidate for preclinical evaluation of both microbicides and pre-exposure prophylactic regimens. The utility of humanized mice to study intravaginal HIV-1 transmission is particularly highlighted by the demonstration that pre-exposure prophylaxis can prevent intravaginal HIV-1 transmission in the BLT mouse model.

Show MeSH
Related in: MedlinePlus