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WO 2019/079361 Al 25 April 2019 (25.04.2019) W 1P O PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2019/079361 Al 25 April 2019 (25.04.2019) W 1P O PCT (51) International Patent Classification: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, C12Q 1/68 (2018.01) A61P 31/18 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, C12Q 1/70 (2006.01) HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (21) International Application Number: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PCT/US2018/056167 OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (22) International Filing Date: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 16 October 2018 (16. 10.2018) TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (30) Priority Data: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 62/573,025 16 October 2017 (16. 10.2017) US TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, ΓΕ , IS, IT, LT, LU, LV, (71) Applicant: MASSACHUSETTS INSTITUTE OF MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TECHNOLOGY [US/US]; 77 Massachusetts Avenue, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Cambridge, Massachusetts 02139 (US). KM, ML, MR, NE, SN, TD, TG). (72) Inventors: SHALEK, Alexander K.; c/o 77 Massachu¬ setts Avenue, Cambridge, Massachusetts 02139 (US). ZIE- Published: GLER, Carly; c/o 77 Massachusetts Avenue, Cambridge, — with international search report (Art. 21(3)) Massachusetts 02139 (US). — with sequence listing part of description (Rule 5.2(a)) (74) Agent: REY, Gertrud U. et al; Johnson, Marcou & Isaacs, LLC, P.O. Box 691, Hoschton, Georgia 30548 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, (54) Title: MARKERS OF ACTIVE HIV RESERVOIR οο · FIG. 1 © (57) Abstract: Embodiments disclosed herein provide a pan-tissue cell atlas of healthy and diseased subjects obtained by single cell sequencing. The present invention discloses novel markers for cell types. Moreover, genes associated with disease, including HIV infection and tuberculosis are identified. The invention provides for diagnostic assays based on gene markers and cell composition, o as well as therapeutic targets for controlling immune regulations and cell-cell communication of the cell types disclosed herein. In addition, novel cell types and methods of quantitating, detecting and isolating the cell types are disclosed. MARKERS OF ACTIVE HIV RESERVOIR CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No. 62/573,025, filed October 16, 2017. The entire contents of the above-identified application are hereby fully incorporated herein by reference. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING [0002] The contents of the electronic sequence listing (BROD-2920WP.ST25.txt"; Size is 8 Kilobytes and it was created on October 9, 2018) is herein incorporated by reference in its entirety. TECHNICAL FIELD [0003] The subject matter disclosed herein is generally directed to a cell atlas of different cell types in healthy and disease states. The subject matter further relates to novel cell specific and disease specific markers. This invention relates generally to compositions and methods identifying and exploiting target genes or target gene products that modulate, control or otherwise influence cell-cell communication, differential expression, immune response in a variety of therapeutic and/or diagnostic indications. BACKGROUND [0004] Immune systems play an essential role in ensuring our health. From decades of laboratory and clinical work, there has been a basic understanding of immune balance and its importance for a healthy immune system. For example, hyperactivity can lead to allergy, inflammation, tissue damage, autoimmune disease and excessive cellular death. On the other hand, immunodeficiency can lead to outgrowth of cancers and the inability to kill or suppress external invaders. The immune system has evolved multiple modalities and redundancies that balance the system, including but not limited to memory, exhaustion, anergy, and senescence. Despite this basic understanding, a comprehensive landscape of immune regulations remains missing. Given the importance of the immune system, a systematic understanding of immune regulations on cell, tissue, and organism levels is crucial for clinicians and researchers to efficiently diagnose and develop treatments for immune system related disease. [0005] Different cells and tissues in a diseased organism are often not impacted at the same level. Analyzing immune regulations with a comprehensive approach allows for identification of cells and tissues that are impacted and that are representative of the disease, interaction between cells, as well as pathways that can be specifically targeted to restore diseased cell or tissues to a normal state. In practice, certain tissues or specimens, for example blood or body fluids, are more easily obtainable than others from a patient. A systematic understanding of immune responses allows clinicians to use easily obtainable tissues as a proxy to diagnose disease and monitor disease state through easily obtainable tissues, and may further allow for treatment or amelioration of symptoms by restoring the state of suppressed immune cells or eliminating severely infected cells, for example, cells impacted with a chronic infection such as HIV infected cells / MTB infected cells. [0006] HIV is a member of the lentivirus family of animal retroviruses, which include the visna virus of sheep and the bovine, feline, and simian immunodeficiency viruses (SIV). HIV preferentially infects CD4 T cells, reverse transcribes its DNA, and integrates into the host genome. During early infection, the host cell experiences a spike in viral load of HIV. Because of such high viral load in plasma, as infected T cells migrate throughout the entire host organism, all tissues can be exposed to HIV, causing profound and often irreversible changes to the adaptive and innate immune systems and establishing a permanent pool of integrated HIV in T cells, known as the HIV reservoir. Standard of care for HIV infection treatment involves anti-retroviral therapies that block various stages of the HIV life cycle. This treatment increases CD4 T cell counts and can decrease HIV levels to below the limit of detection by clinical assays. However, integrated HIV in the HIV reservoir persist and maintain active replication, in low levels of HIV harboring cells and tissues. These persistent HIV reservoir cells remain a critical barrier to cure, and are responsible for ongoing inflammation and pathology even under treatment. SUMMARY [0007] In one aspect, the invention provides a method of modulating a cell or tissue comprising a latent HIV or anti-retroviral therapy (ART)-resistant HIV infection. The method may comprise contacting the cell or tissue with a modulating agent in an amount sufficient to modify the HIV latency or ART-resistance of the cell or tissue as compared to the HIV latency or ART-resistance in the absence of the modulating agent, whereby the HIV latency or ART-resistance of the cell directly influences the latent HIV or ART-resistant HIV infection. [0008] In alternative embodiments, the invention comprises a method of modulating a cell or tissue comprising a hepatitis B or hepatitis C virus infection. [0009] In some embodiments, the modulating of a cell or tissue comprises modulating an immune cell. In some embodiments, the modulating of a cell or tissue comprises modulating a lymph node immune cell. In some embodiments, the modulating of a cell or tissue comprises modulating a T cell or T cell subset. In some embodiments, the modulating of a cell or tissue comprises modulating a CD3 +CD4+PD1 +CXCR4+ T follicular helper cell or a CD45RA CCR7+CD27+ memory T cell. In some embodiments, the modulating of a cell or tissue comprises modulating a gene or product of one or more genes that is enriched for expression in HIV+ cells. In some embodiments, the gene or gene product of two or more genes may be modulated. The one or more genes may be from Table 1 or Table 2 . [0010] The modulating of a cell or tissue may comprise modulating a gene or product of one or more genes that is enriched for expression in HIV cells. As such, the method may comprise modulating a gene or product of two or more genes. The one or more genes may be selected from the genes of Table 3 . [0011] The method may comprise modulating a gene or product of one or more genes that is enriched for expression in HIV+ cells and a gene or product of one or more genes that is enriched for expression in HIV cells. [0012] The T cell or T cell subset may be a CD4+ T cell, and the modulating of a cell or tissue may comprise modulating a gene selected from the group consisting of genes involved in unfolded protein response, HTLV-1 infection, herpes simplex infection, interferon gamma signaling pathway, antigen processing and presentation via MHC class I, positive regulation of apoptotic processes, T cell receptor signaling, virion assembly, and viral transcription. [0013] In another aspect, provided herein is a method of diagnosing a cell or tissue in a subject having a latent HIV or anti-retroviral therapy (ART)-resistant HIV infection.
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