Joint Research Center for Human Retrovirus Infection

Division of International Collaboration Research


Tomáš Hanke (Cross-appointment Professor)

University of Oxford Website
https://www.ndm.ox.ac.uk/principal-investigators/researcher/tomas-hanke


Research

Prof Hanke’s research aims to develop an effective HIV-1 vaccine with emphasis on induction of effective T-cell responses. This is achieved by focusing the vaccine-elicited T cells on the most conserved regions of the HIV-1 proteins, which are common to most global variants and important for virus replicative fitness [1]. This T-cell strategy can be combined with vaccines inducing broadly neutralizing antibodies for the best HIV-1 control [2,3]. Overall, he strives to maintain a balance between basic and translational research. He oversees a busy pre-clinical programme studying T-cell responses [4-7] and exploring novel vaccine modalities [8-10], and co-ordinates a clinical programme assessing candidate HIV-1 vaccines in human volunteers in UK, Europe, US and Africa [11-14]. The 1st-generation conserved-region immunogen HIVconsv employed alternating-clade-consensus regions of the HIV-1 proteome delivered by combinations of plasmid DNA, simian adenovirus and poxvirus MVA [15]. These vaccines were tested in 8 phase 1/2a clinical trials in HIV-1-negative and positive adults in Europe and Africa [16], and induced high frequencies of broadly specific CD8+ T cells capable of in vitro inhibition of 4 major HIV-1 clades A, B, C and D, and in combination with latency-reverting agent provided a signal of drug-free virological control in early-treated patients [17-25]. In May 2013, the programme lost access to the ChAdV63 vector and had to switch to Oxford University owned ChAdOx1. This provided an opportunity to upgrade the HIV-derived protein immunogens based on the 1st-generation clinical data and advances in understanding T-cell protection. The main competitive improvements of the 2nd generation involve combining the four currently leading T-cell strategies into one vaccine design: the focus on vulnerable, functionally conserved regions, which may offer a cross-reaction against many strains of globally circulating viruses [1], rational bioinformatics-assisted computer-optimized bivalent mosaic design with perfect match of 9-amino acid-long epitopes to 80% of the group M variants, inclusion of conserved&protective epitopes in treatment-naïve HIV-1-positive individuals on 4 continents [26-28] and in-humans proven highly immunogenic delivery of the immunogens by the ChAdV-MVA regimen [1]. The tHIVconsvX concept is now in the pipeline for a number of clinical evaluations with two US sites already recruiting. While responses to epitopes in tHIVconsvX regions correlated with good virus control and preservation of the CD4+ T-cell counts [27-29], it remains to be seen whether or not the vaccine modalities presenting the tHIVconsvX immunogens to the immune system elicite T-cell responses, which are robust enough not to be redirected to the non-protective decoy epitopes by incoming or reactivating viruses before these viruses are controled. >>More detail

Oxford-Japan Collaboration

Fine definition of targeted CD8+ T-cell epitopes and their human leucocyte antigen (HLA) class I restriction informs iterative improvements of HIV-1 T-cell vaccine designs and may predict early vaccine success or failure. Lymphocytes from HIVconsv vaccine recipients were used to define the optimum-length target epitopes and their HLA restriction [18]. The protective potential of the 6 conserved HIV regions selected for the 2nd-generation immunogens was demonstrated by studies in 200 treatment-naïve Japanese patients naturally infected with HIV-1 clade B. Using overlapping peptides derived from mosaic 1 and mosaic 2 of the tHIVconsvX immunogens, statistically highly significant correlations of high magnitude and high breadth (number of peptide pools recognized out of 10) of patients’ CD8 T-cell responses with low plasma virus load and high CD4 cell counts were demonstrated and 37 HIV-1-derived epitopes were defined. Of these, 11 were protective in vitro and in vivo correllated with better clinical outcome, strongly endorsing the specificity of the vaccine focusing [27-29]. Despite the non-classical class Ib MHC-E molecule being in the spotlight for HIV-1 vaccine development, until recently there was only one reported HLA-E-binding peptide derived from HIV-1. In an effort to help start understanding the possible functions of HLA-E in HIV-1 infection, we determined novel HLA-E binding peptides derived from the HIV-1 Gag, Pol and Vif proteins [5].

References

1. Hanke, T. (2014). Conserved immunogens in prime-boost strategies for the next-generation HIV-1 vaccines. Expert Opin Biol Ther 14, 601-616.
2. Clutton, G., Carpov, A., Parks, C.L., Dean, H.J., Montefiori, D.C. & Hanke, T. (2014). Optimizing parallel induction of HIV type 1-specific antibody and T-cell responses by multicomponent subunit vaccines. AIDS 28, 2495-2504.
3. Wee, E.G., Moyo, N., Saunders, K.O., LaBranche, C., Donati, F., Capucci, S., et al. Parallel induction of CH505 B-cell ontogeny-guided neutralizing antibodies and tHIVconsvX conserved mosaic-specific T cells against HIV. Mol Ther Methods Clin Dev In press
4. Abdul-Jawad, S., Ondondo, B., van Hateren, A., Gardner, A., Elliott, T., Korber, B., et al. (2016). Increased Valency of Conserved-mosaic Vaccines Enhances the Breadth and Depth of Epitope Recognition. Mol Ther 24, 375-384.
5. Hannoun, Z., Lin, Z., Brackenridge, S., Kuse, N., Akahoshi, T., Borthwick, N., et al. (2018). Identification of novel HIV-1-derived HLA-E-binding peptides. Immunol Lett 202, 65-72.
6. Ternette, N., Block, P.D., Sanchez-Bernabeu, A., Borthwick, N., Pappalardo, E., Abdul-Jawad, S., et al. (2015). Early Kinetics of the HLA Class I-Associated Peptidome of MVA.HIVconsv-Infected Cells. J Virol 89, 5760-5771.
7. Ternette, N., Yang, H., Partridge, T., Llano, A., Cedeno, S., Fischer, R., et al. (2016). Defining the HLA class I-associated viral antigen repertoire from HIV-1-infected human cells. Eur J Immunol 46, 60-69.
8. Kilpelainen, A., Saubi, N., Guitart, N., Moyo, N., Wee, E.G., Ravi, K., et al. (2019). Priming With Recombinant BCG Expressing Novel HIV-1 Conserved Mosaic Immunogens and Boosting With Recombinant ChAdOx1 Is Safe, Stable, and Elicits HIV-1-Specific T-Cell Responses in BALB/c Mice. Front Immunol 10, 923.
9. Moyo, N., Vogel, A.B., Buus, S., Erbar, S., Wee, E.G., Sahin, U., et al. (2018). Efficient induction of T-cell responses against conserved HIV-1 regions by mosaic vaccines delivered as self-amplifying mRNA. Mol Ther Methods Clin Dev 12, 32-46.
10. Wee, E.G., Ondondo, B., Berglund, P., Archer, J., McMichael, A.J., Baltimore, D., et al. (2017). HIV-1 Conserved Mosaics Delivered by Regimens with Integration-Deficient DC-Targeting Lentiviral Vector Induce Robust T Cells. Mol Ther 25, 494-503.
11. Afolabi, M.O., Ndure, J., Drammeh, A., Darboe, F., Mehedi, S.-R., Rowland-Jones, S.L., et al. (2013). A phase I randomized clinical trial of candidate human immunodeficiency virus type 1 vaccine MVA.HIVA administered to Gambian infants. PLoS ONE 8, e78289.
12. Hanke, T., Goonetilleke, N., McMichael, A.J. & Dorrell, L. (2007). Clinical experience with plasmid DNA- and modified vaccinia vaccine Ankara (MVA)-vectored HIV-1 clade A vaccine inducing T cells. J Gen Virol 88, 1-12.
13. Njuguna, I., Reilly, M., Jaoko, W., Gichuhi, C., Ambler, G., Maleche-Obimbo, E., et al. (2014). Infant neutropenia associated with breastfeeding during maternal antiretroviral treatment for prevention of mother-to-child transmission of HIV. Retrovirology 6, 1-5.
14. Njuguna, I.N., Ambler, G., Reilly, M., Ondondo, B., Kanyugo, M., Lohman-Payne, B., et al. (2014). PedVacc 002: A phase I/II randomized clinical trial of MVA.HIVA vaccine administered to infants born to human immunodeficiency virus type 1-positive mothers in Nairobi. Vaccine
15. Letourneau, S., Im, E.-J., Mashishi, T., Brereton, C., Bridgeman, A., Yang, H., et al. (2007). Design and pre-clinical evaluation of a universal HIV-1 vaccine. PLoS ONE 2, e984.
16. Hanke, T. (Submitted). Aiming for protective T-cell responses: A focus on the first generation conserved-region HIVconsv vaccines in clinic. Expert Rev Vaccines
17. Borthwick, N., Ahmed, T., Ondondo, B., Hayes, P., Rose, A., Ebrahimsa, U., et al. (2014). Vaccine-elicited human T cells recognizing conserved protein regions inhibit HIV-1. Mol Ther 22, 464-475.
18. Borthwick, N., Lin, Z., Akahoshi, T., Llano, A., Silva-Arrieta, S., Ahmed, T., et al. (2017). Novel, in-natural-infection subdominant HIV-1 CD8+ T-cell epitopes revealed in human recipients of conserved-region T-cell vaccines. PLoS One 12, e0176418.
19. Fidler, S., Stohr, W., Pace, M., Dorrell, L., Lever, A., Pett, S., et al. (2018). A randomised controlled trial comparing the impact of Antiretroviral Therapy (ART) with a ‘Kick-and-Kill’ approach to ART alone on HIV reservoirs in individuals with primary HIV infection (PHI); RIVER trial. J Int AIDS Soc 21, 155.
20. Hancock, G., Moron-Lopez, S., Kopycinski, J., Puertas, M.C., Giannoulatou, E., Rose, A., et al. (2017). Evaluation of the immunogenicity and impact on the latent HIV-1 reservoir of a conserved region vaccine, MVA.HIVconsv, in antiretroviral therapy-treated subjects. J Int AIDS Soc 20, 1-11.
21. Hancock, G., Yang, H., Yorke, E., Wainwright, E., Bourne, V., Frisbee, A., et al. (2015). Identification of Effective Subdominant Anti-HIV-1 CD8+ T Cells Within Entire Post-infection and Post-vaccination Immune Responses. PLoS Pathog 11, e1004658.
22. Hayton, E.J., Rose, A., Ibrahimsa, U., Del Sorbo, M., Capone, S., Crook, A., et al. (2014). Safety and tolerability of conserved region vaccines vectored by plasmid DNA, simian adenovirus and modified vaccinia virus ankara administered to human immunodeficiency virus type 1-uninfected adults in a randomized, single-blind phase I trial. PLoS One 9, e101591.
23. Mothe, B., Manzardo, C., Snachez-Bernabeau, A., Coll, P., Moron-Lopez, S., Puertas, M.C., et al. (2019). Therapeutic vaccination refocused T-cell responses to conserved regions of HIV-1 in early reated individuals (BCN 01 study). Lancet eClinMed 1, In press.
24. Mothe, B., Moltó, J., Manzardo, C., Coll, J., Puertas, M.C., Martinez-Picado, J., et al. Viral control induced by HIVconsv vaccines & Romidepsin in early treated individuals. in The Conference on Retroviruses and Opportunistic Infections, Vol. Abstract no. 119LB (Seattle, WA, USA, 2017).
25. Mutua, G., Farah, B., Langat, R., Indangasi, J., Ogola, S., Onsembe, B., et al. (2016). Broad HIV-1 inhibition in vitro by vaccine-elicited CD8+ T cells in African adults. Mol Ther Methods Clin Dev 3, 16061.
26. Mothe, B., Llano, A., Ibarrondo, J., Daniels, M., Miranda, C., Zamarreno, J., et al. (2011). Definition of the viral targets of protective HIV-1-specific T cell responses. J Transl Med 9, 208.
27. Murakoshi, H., Akahoshi, T., Koyanagi, M., Chikata, T., Naruto, T., Maruyama, R., et al. (2015). Clinical Control of HIV-1 by Cytotoxic T Cells Specific for Multiple Conserved Epitopes. J Virol 89, 5330-5339.
28. Ondondo, B., Murakoshi, H., Clutton, G., Abdul-Jawad, S., Wee, E.G., Gatanaga, H., et al. (2016). Novel Conserved-region T-cell Mosaic Vaccine With High Global HIV-1 Coverage Is Recognized by Protective Responses in Untreated Infection. Mol Ther 24, 832-842.
29. Zou, C., Murakoshi, H., Kuse, N., Akahoshi, T., Chikata, T., Gatanaga, H., et al. (2019). Effective Suppression of HIV-1 Replication by Cytotoxic T Lymphocytes Specific for Pol Epitopes in Conserved Mosaic Vaccine Immunogens. J Virol 93, e02142-02118.

Division of International Collaboration Research

Tomáš Hanke (Cross-appointment Professor)

University of Oxford Website

https://www.ndm.ox.ac.uk/principal-investigators/researcher/tomas-hanke

Research

Prof Hanke’s research aims to develop an effective HIV-1 vaccine with emphasis on induction of effective T-cell responses. This is achieved by focusing the vaccine-elicited T cells on the most conserved regions of the HIV-1 proteins, which are common to most global variants and important for virus replicative fitness [1]. This T-cell strategy can be combined with vaccines inducing broadly neutralizing antibodies for the best HIV-1 control [2,3].

Overall, he strives to maintain a balance between basic and translational research. He oversees a busy pre-clinical programme studying T-cell responses [4-7] and exploring novel vaccine modalities [8-10], and co-ordinates a clinical programme assessing candidate HIV-1 vaccines in human volunteers in UK, Europe, US and Africa [11-14].

The 1st-generation conserved-region immunogen HIVconsv employed alternating-clade-consensus regions of the HIV-1 proteome delivered by combinations of plasmid DNA, simian adenovirus and poxvirus MVA [15]. These vaccines were tested in 8 phase 1/2a clinical trials in HIV-1-negative and positive adults in Europe and Africa [16], and induced high frequencies of broadly specific CD8+ T cells capable of in vitro inhibition of 4 major HIV-1 clades A, B, C and D, and in combination with latency-reverting agent provided a signal of drug-free virological control in early-treated patients [17-25].

In May 2013, the programme lost access to the ChAdV63 vector and had to switch to Oxford University owned ChAdOx1. This provided an opportunity to upgrade the HIV-derived protein immunogens based on the 1st-generation clinical data and advances in understanding T-cell protection. The main competitive improvements of the 2nd generation involve combining the four currently leading T-cell strategies into one vaccine design: the focus on vulnerable, functionally conserved regions, which may offer a cross-reaction against many strains of globally circulating viruses [1], rational bioinformatics-assisted computer-optimized bivalent mosaic design with perfect match of 9-amino acid-long epitopes to 80% of the group M variants, inclusion of conserved&protective epitopes in treatment-naïve HIV-1-positive individuals on 4 continents [26-28] and in-humans proven highly immunogenic delivery of the immunogens by the ChAdV-MVA regimen [1]. The tHIVconsvX concept is now in the pipeline for a number of clinical evaluations with two US sites already recruiting.

While responses to epitopes in tHIVconsvX regions correlated with good virus control and preservation of the CD4+ T-cell counts [27-29], it remains to be seen whether or not the vaccine modalities presenting the tHIVconsvX immunogens to the immune system elicite T-cell responses, which are robust enough not to be redirected to the non-protective decoy epitopes by incoming or reactivating viruses before these viruses are controled.

>>More detail

Oxford-Japan Collaboration

Fine definition of targeted CD8+ T-cell epitopes and their human leucocyte antigen (HLA) class I restriction informs iterative improvements of HIV-1 T-cell vaccine designs and may predict early vaccine success or failure. Lymphocytes from HIVconsv vaccine recipients were used to define the optimum-length target epitopes and their HLA restriction [18].

The protective potential of the 6 conserved HIV regions selected for the 2nd-generation immunogens was demonstrated by studies in 200 treatment-naïve Japanese patients naturally infected with HIV-1 clade B. Using overlapping peptides derived from mosaic 1 and mosaic 2 of the tHIVconsvX immunogens, statistically highly significant correlations of high magnitude and high breadth (number of peptide pools recognized out of 10) of patients’ CD8 T-cell responses with low plasma virus load and high CD4 cell counts were demonstrated and 37 HIV-1-derived epitopes were defined. Of these, 11 were protective in vitro and in vivo correllated with better clinical outcome, strongly endorsing the specificity of the vaccine focusing [27-29].

Despite the non-classical class Ib MHC-E molecule being in the spotlight for HIV-1 vaccine development, until recently there was only one reported HLA-E-binding peptide derived from HIV-1. In an effort to help start understanding the possible functions of HLA-E in HIV-1 infection, we determined novel HLA-E binding peptides derived from the HIV-1 Gag, Pol and Vif proteins [5].

References

1. Hanke, T. (2014). Conserved immunogens in prime-boost strategies for the next-generation HIV-1 vaccines. Expert Opin Biol Ther 14, 601-616.

2. Clutton, G., Carpov, A., Parks, C.L., Dean, H.J., Montefiori, D.C. & Hanke, T. (2014). Optimizing parallel induction of HIV type 1-specific antibody and T-cell responses by multicomponent subunit vaccines. AIDS 28, 2495-2504.

3. Wee, E.G., Moyo, N., Saunders, K.O., LaBranche, C., Donati, F., Capucci, S., et al. Parallel induction of CH505 B-cell ontogeny-guided neutralizing antibodies and tHIVconsvX conserved mosaic-specific T cells against HIV. Mol Ther Methods Clin Dev In press

4. Abdul-Jawad, S., Ondondo, B., van Hateren, A., Gardner, A., Elliott, T., Korber, B., et al. (2016). Increased Valency of Conserved-mosaic Vaccines Enhances the Breadth and Depth of Epitope Recognition. Mol Ther 24, 375-384.

5. Hannoun, Z., Lin, Z., Brackenridge, S., Kuse, N., Akahoshi, T., Borthwick, N., et al. (2018). Identification of novel HIV-1-derived HLA-E-binding peptides. Immunol Lett 202, 65-72.

6. Ternette, N., Block, P.D., Sanchez-Bernabeu, A., Borthwick, N., Pappalardo, E., Abdul-Jawad, S., et al. (2015). Early Kinetics of the HLA Class I-Associated Peptidome of MVA.HIVconsv-Infected Cells. J Virol 89, 5760-5771.

7. Ternette, N., Yang, H., Partridge, T., Llano, A., Cedeno, S., Fischer, R., et al. (2016). Defining the HLA class I-associated viral antigen repertoire from HIV-1-infected human cells. Eur J Immunol 46, 60-69.

8. Kilpelainen, A., Saubi, N., Guitart, N., Moyo, N., Wee, E.G., Ravi, K., et al. (2019). Priming With Recombinant BCG Expressing Novel HIV-1 Conserved Mosaic Immunogens and Boosting With Recombinant ChAdOx1 Is Safe, Stable, and Elicits HIV-1-Specific T-Cell Responses in BALB/c Mice. Front Immunol 10, 923.

9. Moyo, N., Vogel, A.B., Buus, S., Erbar, S., Wee, E.G., Sahin, U., et al. (2018). Efficient induction of T-cell responses against conserved HIV-1 regions by mosaic vaccines delivered as self-amplifying mRNA. Mol Ther Methods Clin Dev 12, 32-46.

10. Wee, E.G., Ondondo, B., Berglund, P., Archer, J., McMichael, A.J., Baltimore, D., et al. (2017). HIV-1 Conserved Mosaics Delivered by Regimens with Integration-Deficient DC-Targeting Lentiviral Vector Induce Robust T Cells. Mol Ther 25, 494-503.

11. Afolabi, M.O., Ndure, J., Drammeh, A., Darboe, F., Mehedi, S.-R., Rowland-Jones, S.L., et al. (2013). A phase I randomized clinical trial of candidate human immunodeficiency virus type 1 vaccine MVA.HIVA administered to Gambian infants. PLoS ONE 8, e78289.

12. Hanke, T., Goonetilleke, N., McMichael, A.J. & Dorrell, L. (2007). Clinical experience with plasmid DNA- and modified vaccinia vaccine Ankara (MVA)-vectored HIV-1 clade A vaccine inducing T cells. J Gen Virol 88, 1-12.

13. Njuguna, I., Reilly, M., Jaoko, W., Gichuhi, C., Ambler, G., Maleche-Obimbo, E., et al. (2014). Infant neutropenia associated with breastfeeding during maternal antiretroviral treatment for prevention of mother-to-child transmission of HIV. Retrovirology 6, 1-5.

14. Njuguna, I.N., Ambler, G., Reilly, M., Ondondo, B., Kanyugo, M., Lohman-Payne, B., et al. (2014). PedVacc 002: A phase I/II randomized clinical trial of MVA.HIVA vaccine administered to infants born to human immunodeficiency virus type 1-positive mothers in Nairobi. Vaccine

15. Letourneau, S., Im, E.-J., Mashishi, T., Brereton, C., Bridgeman, A., Yang, H., et al. (2007). Design and pre-clinical evaluation of a universal HIV-1 vaccine. PLoS ONE 2, e984.

16. Hanke, T. (Submitted). Aiming for protective T-cell responses: A focus on the first generation conserved-region HIVconsv vaccines in clinic. Expert Rev Vaccines

17. Borthwick, N., Ahmed, T., Ondondo, B., Hayes, P., Rose, A., Ebrahimsa, U., et al. (2014). Vaccine-elicited human T cells recognizing conserved protein regions inhibit HIV-1. Mol Ther 22, 464-475.

18. Borthwick, N., Lin, Z., Akahoshi, T., Llano, A., Silva-Arrieta, S., Ahmed, T., et al. (2017). Novel, in-natural-infection subdominant HIV-1 CD8+ T-cell epitopes revealed in human recipients of conserved-region T-cell vaccines. PLoS One 12, e0176418.

19. Fidler, S., Stohr, W., Pace, M., Dorrell, L., Lever, A., Pett, S., et al. (2018). A randomised controlled trial comparing the impact of Antiretroviral Therapy (ART) with a ‘Kick-and-Kill’ approach to ART alone on HIV reservoirs in individuals with primary HIV infection (PHI); RIVER trial. J Int AIDS Soc 21, 155.

20. Hancock, G., Moron-Lopez, S., Kopycinski, J., Puertas, M.C., Giannoulatou, E., Rose, A., et al. (2017). Evaluation of the immunogenicity and impact on the latent HIV-1 reservoir of a conserved region vaccine, MVA.HIVconsv, in antiretroviral therapy-treated subjects. J Int AIDS Soc 20, 1-11.

21. Hancock, G., Yang, H., Yorke, E., Wainwright, E., Bourne, V., Frisbee, A., et al. (2015). Identification of Effective Subdominant Anti-HIV-1 CD8+ T Cells Within Entire Post-infection and Post-vaccination Immune Responses. PLoS Pathog 11, e1004658.

22. Hayton, E.J., Rose, A., Ibrahimsa, U., Del Sorbo, M., Capone, S., Crook, A., et al. (2014). Safety and tolerability of conserved region vaccines vectored by plasmid DNA, simian adenovirus and modified vaccinia virus ankara administered to human immunodeficiency virus type 1-uninfected adults in a randomized, single-blind phase I trial. PLoS One 9, e101591.

23. Mothe, B., Manzardo, C., Snachez-Bernabeau, A., Coll, P., Moron-Lopez, S., Puertas, M.C., et al. (2019). Therapeutic vaccination refocused T-cell responses to conserved regions of HIV-1 in early reated individuals (BCN 01 study). Lancet eClinMed 1, In press.

24. Mothe, B., Moltó, J., Manzardo, C., Coll, J., Puertas, M.C., Martinez-Picado, J., et al. Viral control induced by HIVconsv vaccines & Romidepsin in early treated individuals. in The Conference on Retroviruses and Opportunistic Infections, Vol. Abstract no. 119LB (Seattle, WA, USA, 2017).

25. Mutua, G., Farah, B., Langat, R., Indangasi, J., Ogola, S., Onsembe, B., et al. (2016). Broad HIV-1 inhibition in vitro by vaccine-elicited CD8+ T cells in African adults. Mol Ther Methods Clin Dev 3, 16061.

26. Mothe, B., Llano, A., Ibarrondo, J., Daniels, M., Miranda, C., Zamarreno, J., et al. (2011). Definition of the viral targets of protective HIV-1-specific T cell responses. J Transl Med 9, 208.

27. Murakoshi, H., Akahoshi, T., Koyanagi, M., Chikata, T., Naruto, T., Maruyama, R., et al. (2015). Clinical Control of HIV-1 by Cytotoxic T Cells Specific for Multiple Conserved Epitopes. J Virol 89, 5330-5339.

28. Ondondo, B., Murakoshi, H., Clutton, G., Abdul-Jawad, S., Wee, E.G., Gatanaga, H., et al. (2016). Novel Conserved-region T-cell Mosaic Vaccine With High Global HIV-1 Coverage Is Recognized by Protective Responses in Untreated Infection. Mol Ther 24, 832-842.

29. Zou, C., Murakoshi, H., Kuse, N., Akahoshi, T., Chikata, T., Gatanaga, H., et al. (2019). Effective Suppression of HIV-1 Replication by Cytotoxic T Lymphocytes Specific for Pol Epitopes in Conserved Mosaic Vaccine Immunogens. J Virol 93, e02142-02118.