Episode 321: HIV Cure revisited part 1: how to tackle the reservoir
After 3 years of focus on COVID, I was reminded of my previous life, by a short paper in Nature Briefing (321-1) and Nat Med (321-2) about the “Düsseldorf patient”, the third HIV(+) person in the world with sustained evidence of HIV cure, after the “Berlin patient” (Timothy Brown, who recently died free of HIV) and the “London patient” (Adam Castillejo). All three were treated for acute myeloid leukemia with a complete destruction of their own bone marrow, which was replace by hematopoietic stem cell transplantation from a donor with homozygous delta-32 deletion of CCR5, leading to T cells and macrophages/dendritic cells, which are resistant to HIV. Unfortunately, until now, no other strategy was able to induce real cure.
To put these results into perspective, I gathered some recent review on the topic. In this first part, I summarize a nice introductory review first and then I will try and explain how concepts about the viral reservoir have evolved and review the two main strategies “shock and kill” versus “block and lock”. There is a large number of candidate-drugs, but no real clinical success yet. Besides this “pharmacological” approach, the hope of the “genetic approach nowadays is on the CRISPR-Cas tools that could inactivate the viral reservoir on one hand and in the next Episode (322).
For papers see:
- Overall introduction is by Shuang Li in the Chinese Medical Journal 2023 (Ep 321-3)
Innate immune response and HIV reservoir (Ep 321-3)
(A) HIV reservoirs. HIV reservoirs are established early in HIV infection and hide in immune-privileged anatomic sites, including the brain, bone marrow, lungs, lymph nodes, and GALT.
(B) Macrophages and HIV reservoirs. Host restriction factors, including SAMHD1, APOBEC3, and MX2, can influence HIV latency in macrophages by inhibiting RT.
(C) Dendritic cell- Natural Killer cell crosstalk. DCs are activated by HIV; secrete pro-inflammatory cytokines, including IL-12, IL-15, and IFNs; and stimulate NK cells. Activated NK cells secrete IFN-g to promote DC maturation and Th1 immunity. DC–NK cell crosstalk is attenuated in HIV infection.
(D) DCs and HIV reservoirs. Viral restriction factors play an important role in HIV reservoirs in DCs, including SAMHD1, IFITM proteins, TRIM5a, Tetherin, and APOBEC3. HIV can counteract the immune response induced by these host restriction factors by encoding viral accessory proteins, including Vpr and Vif, which can antagonize APOBEC3, and Vpu and nef, which can antagonize Tetherin.
(E) NK cells and HIV reservoirs. NK cells can recognize and eliminate HIV-infected cells through many different mechanisms, mainly cytokine secretion, ADCC, cytotoxic granule exocytosis, and death receptor pathway activity, which may be effective for reducing the size of the latent HIV reservoir and become a promising strategy for achieving a functional HIV cure.
Abbreviations: ADCC: Antibody-dependent cellular cytotoxicity; APOBEC3: Apolipoprotein B Editing Complex3; CCR5: C-C chemokine receptor 5; CD4:cluster of differentiation 4; DCs: Dendritic cells; GALT: Gut-associated lymphoid tissue; HIV: Human immunodeficiency virus; HLA-B: Human leukocyte antigen-B; IFITM: Interferon-induced transmembrane; IFN-g: Interferon g; IL-12: Interleukin-12; KIR: Killer immunoglobulin-like receptors; MX2: Myxovirus-resistance protein 2; NK: Natural killer; NKG2DL: Natural killer group 2 member D ligand; NKG2D: Natural killer group 2D; RT: Reverse transcription; SAMHD1: Sterile a-motif/histidine-aspartate domain-containing protein 1; Tetherin: Bone marrow stromal antigen 2; Th1 immunity: T helper 1 immunity; TNF: Tumor necrosis factor; TRIM5a: Tripartite motif containing 5 alpha.
Immune interventions for HIV cure (Ep 321-3)
A) “Shock” HIV out of hiding. HIV latency in reservoirs is reversed, leading to increases in viral gene expression and viral protein production.
(B) Innate immunity-based interventions for HIV cure. TLR7 agonists and pDCs reactivate HIV-infected cells. HIV-infected cells can be recognized and killed by CTLs and NK cells. MoDC induce CTL and CD4+ T cell responses through Ag presentation. DC-based immunotherapeutic vaccines also involve CD40L, which can enhance DC maturation, interleukin(IL)-12p70 (IL-12p70) production and Ag presentation.
(C) T cell-based interventions for HIV cure. CTL-mediated immunotherapy plays a critical role in eliminating the HIV reservoir. CAR-T cells target HIV binding sites on the surface of reactivated reservoir cells and secrete granzymes and cytokines to kill HIV-infected cells.
(D) Antibody-based interventions for HIV cure. HIV-specific bNAbs can bind withdifferent epitopes of HIV Env and promote the elimination of HIV reservoirs. Bispecific Abs can simultaneously bind with two different Ag binding sites or epitopes with different inhibitory effects on HIV Env to produce immune responses. DART proteins can improve the recognition of HIV Env on the surface of infected cells and recruit effector cells to eliminate infected cells.
(E) Hematopoietic stem cell transplantation for HIV cure. Allo-HSCT with homozygous CCR5D32 donor cells may achieve HIV remission, further supporting the development of functional HIV cures. The graft-versus-host effect may be a key factor in achieving a sterilizing cure of HIV infection after allo-HSCT.
Abbreviations: Abs: Antibodies; ADCC: Antibody-dependent cellular cytotoxicity; Ag: Antigen; allo-HSCT: Allogeneic hematopoietic stem cell transplantation; bNAbs: Broadly neutralizing Abs; CAR-T: Chimeric antigen receptor T; CCR5: C-C chemokine receptor 5; CD40: Cluster of differentiation 40; CD40L: CD40 ligand; CTLs: Cytotoxic T lymphocytes; DART: Dual-affinity retargeting; DC: Dendritic cell; DNA: Deoxyribonucleic acid; FcgR: Fc gamma receptor; HIV: Human immunodeficiency virus; HIV Env: HIV envelope; IFNg: Interferon gamma; IL-2: Interleukin-2; MHC: Major histocompatibility complex; MoDC: Monocyte-derived DCs; NK: Natural killer; pDCs: Plasmacytoid DCs; PLWH: People living with HIV; RNA: Ribonucleic acid; TCR: T-cell receptor; TLR7: Toll-like receptor 7; TNF-a: Tumor necrosis factor-alpha.
- Evolving insights into the nature of the viral reservoir
Ep 321-4: Alexander Pasternak Current Opinion Virology 2023
Previously, we considered persistence of transcriptionally silent proviruses in a stable latent reservoir that is invisible to the immune system.
Now we recognize that HIV also persists by resistance to the immune clearance, which appears to play a surprisingly prominent role in shaping the reservoir.
Classification of HIV persistence in ART-treated PLWH according to the genetic intactness and transcription-translation competence of the persistent proviruses.
(a) Genetically intact and transcription- and translation-competent proviruses form the HIV reservoir. In vivo, these proviruses may either be transcriptionally silent or produce one or more cell-associated HIV RNA species; upon ex vivo stimulation, they are activated to the productive infection. Most reservoir cells are currently believed to be latently infected, but a fraction of latently infected cells is constantly reactivated from latency to produce virus in vivo.
(b) Genetically defective but transcription- and/or translation-competent proviruses (‘zombie proviruses’) are not part of the reservoir but can produce viral (or novel) RNA and proteins, potentially participating in the residual HIV pathogenesis on ART.
(c) Some genetically intact proviruses are integrated in a chromatin context that permanently represses transcription (‘deep latency’) and are transcription- and hence replication-defective. These proviruses are not part of the reservoir.
(d) Some proviruses harbor profound genetic defects that preclude viral transcription
Categories of persistent intact proviruses in PLWH on ART.
Genetically intact proviruses can be ex vivo replication-competent (i.e. can be induced to release infectious virus after one or more rounds of VOA = viral outgrowth assay), in vivo rebound-competent, both replication- and rebound-competent, or none of the above. The dashed border of the rebound-competent reservoir depicts the fluctuating nature of this fraction of intact proviruses in time, which reflects changes in the host immune pressure. The relative sizes of the circles are arbitrary and not meant to reflect the relative numbers of the intact, replication-competent, and rebound-competent proviruses.
Therefore: instead of persistence of transcriptionally silent proviruses in a stable latent reservoir that is invisible to the immune system except for occasional reactivation, HIV is now believed to persist by dynamic proliferation and contraction of cellular clones that can harbor both intact and defective, and both transcriptionally silent and active proviruses
In some PLWH on prolonged ART and natural controllers, the reservoir seems to have been shaped by the immune pressure to such an extent that it consists predominantly of deeply latent proviruses
However, in many others under ART, expanded clones that contain intact and transcriptionally active proviruses, termed ‘the loud minority’, persist for years and may even sometimes cause a persistent detectable plasma viremia. Upon interruption of cART, this replication-competent reservoir will, sooner or later, give rise to viral rebound.
Implication for cure strategies:
- Previously: emphasis on “shock and kill”: latency reversal and immune killing (e.g. by cytolytic T cells)
- Now more emphasis on “block and lock” = induction of “deep latency” + immune-modulatory agents (e.g. combinations of broad neutralizing antibodies
Ep 321-5: Alejandro de Gea-Grela Pathogens 2023
Simplified anatomical distribution of the viral reservoir
Different cell lines contain viral genetic material integrated into their genome: CD4 T cells are the most prominent, with the memory cell lineage being of particular relevance. However, other cell assemblies also act as a viral reservoir, such as dendritic cells/macrophages, epithelial cells or adipose tissue cells.
In terms of anatomical distribution, the reservoir in lymph nodes stands out, especially at the level of GALT (lymphoid tissue associated with the intestine), with other locations, such as the spleen or microglia at the level of the central nervous system
Some of the cellular reservoirs are “hidden” e.g. microglia and astrocytes in CNS; T follicular helper cells in germinal centers of lymph nodes; adipose tissue etc. It might be very difficult to reach these sites by either anti-retroviral drugs, latency reversal drugs, NK cells, cytolytic T cells, antibodies etc…
Clonal replication in the latent viral reservoir in lymph nodes.
Following an antigenic stimulus, or simply following a homeostatic replication cycle (= without exogenous stimulation), cells containing integrated viral DNA material would enter into viral replication cycles, which contributes to maintaining the latent viral reservoir and would be the cause of persistent low-level viremia despite ART and viral rebound after ART cessation.
Persistent viral replication in lymph nodes.
Adequate levels of ART in the blood cells block viral replication, thus maintaining undetectable plasma viral loads.
However, at the same time, ART does not reach adequate levels in lymph nodes, so there are complete cycles of viral
replication and new cell infections at this level.
- Shock and kill versus block and lock
Ep 321-6: Eric Abner Antivir Res 2019 Schock and kill needs revision
Ep 321-7: Benni Vargas Pathogens 2022 The Block and lock approach
Visualization of “shock and kill” and “block and lock” approaches.
Following an infection event, the majority of infected CD4+ T cells die, but a minor subset survives, harboring latent proviruses.
The clonal expansion of the provirus is driven by the proliferation of these latently infected cells.
The curative “shock and kill” strategy aims to decrease the functional HIV reservoir by pharmacologically reactivating proviral transcription, with the hope on the elimination of infected cells via immune clearance and HIV-cytolysis.
Alternatively, persistent “block and lock” therapy is projected to fully inhibit the proviral expression and the drive the infection into a state of deep latency.
Both the of the depicted therapies should be applied during virus-suppressive combinatory antiretroviral therapy (cART). If they are really successful, cART could be stopped without viral rebound.
Mechanisms of action of different classes of Latency reversal Agents (LRAs) (Ep 321-6)
The most potent signal transduction for HIV reactivation is carried out by cytokines and other activators signaling through various immune receptors present on the infected cell surface. Among other signal transduction pathways, their stimulation canonically leads to the
activation of NF-κB, STAT5 and NFAT transcription factors), which localize to the cell nucleus and participate directly in HIV reactivation.
Certain membrane TLR agonists, SMAC mimetics and PKC agonists activate cytosolic NF-κB as well, while the exact mechanism of action of endosomal TLR still remains to be confirmed.
Within the cytosol:
- Proteasome inhibitors induce the accumulation of HSP90, which in turn activates various transcription factors.
- Disulfiram reduces PTEN protein levels, allowing the activated Akt kinase to localizes to the nucleus, where it participates in releasing P-TEFb from the repressive 7SK snRNP complex. (Middle right)
In the nucleus:
- The release of P-TEFb complex can additionally be induced BETis. The released P-TEFb kinase assists in the regulation of RNA Pol-II dependent elongation. (Upper right)
- Amongst non-histone modifying mechanisms, reducing DNA methylation in the LTR or the eviction of repressive transcription factors like RUNX1 is known to result in HIV reactivation.
- The repressive bromodomain proteins Brd2 and Brd4 can be evicted by the use of BETis.
- Finally, inhibition of the BAF complex leads to its displacement from the LTR, thus allowing the release of Nuc-1. (Lower right)
- Proviral reactivation can also be induced by manipulating the post-translational modifications of the core histone tails via HDACis, HMTis and Na-Cro.
- HIV transcription can further be induced by inhibiting KAT5, which is required for H4-acetylation and Brd4 binding.
Abbreviations: TLR, Toll-like receptor; NF-κB, Nuclear factor kappa-light-chain-enhancer of activated B cells; HSP90, Heat shock protein 90; HSF1, Heat shock factor 1; NFAT, Nuclear factor of activated T-cells; STAT5, Signal transducer and activator of transcription 5,
SMACm, Second mitochondrial-derived activator of caspases mimetic; Akt, protein kinase B; PTEN, Phosphatase and tensin homolog; HEXIM1, Hexamethylene bisacetamide inducible 1; P-TEFb, Positive transcription elongation factor b; 7SK snRNP, 7SK small nuclear ribonucleoprotein complex; CTD, C-terminal domain; Brd, Bromodomain containing protein; DNMT, DNA methyltransferase; RUNX1, Runt-related transcription factor 1; BETi, Bromodomain and extraterminal domain inhibitor; BAF, BRG1-or HBRM-associated factors; 5-Aza-CdR, 5-aza-2′-deoxycytidine; TFs, transcription factors; HDAC, histone deacetylase; KAT, Lysine acetyltransferase; HMT, histone methyltransferase; Nuc, nucleosome; Pol-II, Polymerase II; KAT5, Lysine acetyltransferase 5; TSS, transcription start site; P, phosphorylation; Ac, acetylation; Cr, crotonylation; Met, methylation.
Synergistic reactivation of HIV-1 between different categories of latency reversal agents (LRAs). (Ep 321-6)
Curved lines between the different classes of compounds highlight synergies that have been demonstrated either in vitro/ex vivo to date between LRAs.
Abbreviations: PTM, post-translational modification; Resver., Resveratrol; PIs, Protease inhibitors; DNMTi, DNA-methyltransferase inhibitors; BAFi, BRG1/BRM associated factor inhibitor; HMTi, histone methyltransferase inhibitors; PKCa,
Protein kinase C agonists; SMACm, SMAC mimetics; Na-Cro, sodium crotonate; TLR, Toll-like receptor; BETi, Bromodomain and extraterminal domain inhibitor.
Proposed mechanisms of Latency Promoting Agents (LPAs) for “block and lock” therapy. (Ep 321-6)
The chemical inhibition of the trans-membrane HSP90 protein leads to the suppression of both NF-κB dependent pathways and sequesters HSF1 transcription factor to the cytosol.
NF-κB inhibition can also be achieved with mTOR and PKC inhibitors
The inhibition of mTOR complex by Torin 1 and Triptolide can further impede HIV-1 by inducing Tat degradation through
Inhibition of the JAK-STAT pathway with extracellular JAK-inhibitors limits the STAT5-dependent transcription.
Intranuclearly, didehydro-Cortistatin A (dCA) binds directly into the active site of Tat, suppressing its binding from viral TAR RNA.
Dashed arrows represent inhibited pathways.
Abbreviations: mTOR, Mammalian target of rapamycin; PKC, Protein kinase C; HSP90, Heat-shock protein 90; HSF1, Heat-shock factor 1; NF-κB, Nuclear factor kappa-light-chain-enhancer of activated B cells; FACT, Facilitates chromatin transcription; LTR, Long terminal repeat; Nuc, nucleosome
Chemical structure and mode of action of possible block and lock agents (Ep 321-7)
Two types are most HIV-specific:
- Tat inhibitors (dCa or dihydro-cortistatin A)
- Allosteric Integrase Inhibitors (ALLINIs), also referred to as LEDGINs, non-catalytic-site integrase inhibitors (NCINI) or multimeric integrase inhibitors (MINI),
Critical evaluation of these strategies:
- Latency reversal has shown results in vitro, but clinical trials with single compounds, even in combination with immune therapy, have not convincingly shown a decrease of viral reservoir
- LRAs should reactivate the total HIV-1 reservoir, but this is not realized until now in vivo due to
- the broad integrational landscape of the provirus,
- condensed chromatin state of resting T cells,
- sequestration of necessary transcription factors and
- the physiological heterogeneity of the host cells.
- LRA should not completely reactivate the T cells, because this could lead to “cytokine storm.
- LRA do not provide the “kill”: complementary immune therapy is needed, but not yet realized
Could a combination of highly specific LRA, possibly in sequential order, and supplemented with immuno-therapy offer perspective on a (partial) cure or remission?
- Block and lock = less advanced, only in vitro results. Has similar challenges as LRA
- Should target also deep tissue reservoirs: difficult to reach
- Should not interfere with normal cell metabolism
The HIV-specific inhibitors (Tat and Allosteric Integrase Inhibitors) seem most promising
- BCL-2 and JAK-STAT INHIBITORS to reduce HIV reservoir?
Ep 321-7: Monica Reece Front Immunol Dec 2022: Repurposing BCL-2 and JAK ½ inhibitors for HIV Cure
The BCL-2 inhibitors (Venetoclax) and Jak ½ inhibitors (Ruxolitinib, Baricitinb and others) are orally available and FDA approved for treatment of some leukemias (because they reduce life span of activated cells) and for severe inflammation in the context of rheumatoid arthritis or COVID-19.
In this paper, it is explained how these compounds could interfere with molecular mechanisms that maintain HIV reservoir.
Activation of the Jak STAT pathway by pro-inflammatory cytokines (like those produced in viral infection) produces dimerized pSTAT5 that directly upregulates BCL-2, a pro-survival factor, resulting in long-lived cells harboring HIV-1 DNA.
- Jak inhibitors (ruxolitinib, baricitinib, tofacitinib) can block the BCL-2 cascade upstream.
- Venetoclax, FDA approved BCL-2 selective BCL-2 homology 3 (BH3) mimetic, prevents BCL-2 sequestration of BH3. Free BH3 is then able to interact with pro-apoptotic proteins (BAK, BAX, BIM, BAD) to perform mitochondrial outer membrane permeabilization (MOMP) thereby releasing cytochrome C. Cytochrome C interacts with pro-caspase9/apoptotic protease activating factor 1 (APAF-1) to initiate a caspase cascade that culminates in apoptotic cell death
Cytokines produced subsequently from tumors and HIV-1-infected cells initiate the Jak STAT pathway leading to upregulation of pro-survival and pro-senescence factors like BCL-2 and IL-10.
Jak inhibitors (ruxolitinib, baricitinib, tofacitinib) prevent upregulation of these factors upstream while BCL-2 homology 3 (BH3) mimetics like venetoclax prevent BCL-2 function downstream, as shown in Figure 1.
IL-10 promotes cellular senescence through upregulation of BCL-2 and programmed death protein 1 (PD-1). Senescent cells express latency-associated peptide (LAP) and glycoprotein A repetitions predominant (GARP) which undergo protein cleavage and release bound TGF-b. TGF-b upregulates promyelocytic leukemia protein (PML) which associates to protein phosphatase 2A (PP2A) thereby sequestering DNA damage inducible transcript 4 (DDIT4) and inhibiting Ak strain transforming (AKT) kinase, ultimately resulting in inhibition of the mammalian target of rapamycin (mTOR) pathway which is responsible for T cell differentiation. In parallel, PML stabilizes forkhead box O4 (FOXO4) and O3 (FOXO3). FOXO4 binds p53 to downregulate pro-apoptotic machinery. FOXO3 upregulates PD-1 expression on CD8+ T cells which blocks T cell differentiation and impairs cytotoxic ability. This creates a phenotype of long-lived senescent cells and T cells with impaired cytotoxic/killing potential further maintaining the HIV-1 reservoir.
Ep 321-9: Vincent Marconi CID 2021 Phase 2 trial of Ruxolitinib reduced markers of CD4 T cell activation and cell survival, but had no significant influence on HIV reservoir
Ruxolitinib decreased biomarkers associated with poor outcomes for PWH during a 5 week treatment, including:
- T-cell activation, immune dysregulation, and inflammation:(CD3+/CD4+/HLA-DR+/CD38+, D3+/CD4+/CD25Hi+/CD127–
- cellular lifespan: CD3+/CD4+/BCL2+
- and intestinal translocation/inflammation/homing: CD3+/CD4+/α4β7+, IL-18, sCD14.
Unfortunately, no significant effect on reservoir markers
Clearly, this strategy is easy to further explore (FDA approved oral compounds), it may reduce “immune activation”, which has a role in pathogenesis of long-term complications of ART PLWH and may also have a role in viral persistence, but it does not seem to be able to eradicate HIV on its own. Hence combination therapy is warranted.
- CRISPR-CAS to ERADICATE HIV and/or RENDER CELLS RESISTANT? (Ep 321-10 Hussein Int J Mol Sc 2023)
The CRISPR-Cas system contains a nuclease, named Cas, which binds to a short CRISPR RNA (crRNA) that targets complementary DNA or RNA sequences: Cas9 and Cas12 target DNA; Cas13 targets RNA
Different CRISPR-Cas proteins (Cas9,Cas12, and Cas13), their target molecules, and the cleavage mechanisms
The protospacer adjacent motif (PAM) required as DNA target for Cas9 and Cas12 cleavage in addition to the protospacer flanking site (PFS) required for some Cas13 RNA target are shown in pink.
The crRNAs are depicted in red for each CRISPR-Cas system.
When double-strand DNA breaks (DSBs) are created by Cas9 and Cas12, cellular DNA repair mechanisms are induced, either non-homologous end joining (NHEJ) or homology-directed repair (HDR). HDR requires a donor DNA template and can result in precise gene editing, while NHEJ is an error-prone repair process that introduces mutations, insertions, and deletions (INDELS, shown in orange). It is the NHEJ mechanism that inactivates a host gene or the integrated HIV DNA, according to the specificity of the cfRNA
The Cas13 recognition and cleavage of a target RNA transcript leads to its degradation and possibly the non-specific degradation of nearby transcripts (collateral RNA cleavage)
CRISPR-Cas-based strategies have been applied
- as direct antivirals by mutating or excising the integrated proviral HIV DNA
- or indirectly by disabling viral receptors for cell entry (e.g. CCR5 deletion)
HIV attack with CRISPR-Cas-based inhibitors.
HIV recognizes and binds to the host receptors CXCR4 and/or CCR5 in CD4+ T cells, and fuses with the cellular membrane. Subsequently,
viral RNA is released into the cytoplasm. This viral RNA is reverse transcribed into DNA that integrates into the host genome. In the nucleus, this proviral DNA is transcribed and transported to the cytoplasm where it is translated. Viral proteins are expressed and are then packaged as well as assembled into a viral core structure that buds from infected cells and is released as new virions.
CRISPR-Cas gene editing strategies (blue scissors) can be designed to target viral DNA and RNA via the specificity of the crRNA, associated with either Cas9/12 or Cas13 respectively.
Other potential targets include the host DNA encoding for proteins that facilitate steps of the HIV replication cycle, such as the main CD4 receptor and co-receptors (CCR5 and CXCR4).
Challenges and potential solutions
- Combinatorial approach is better than single
- Single approaches consist of targeting viral genes with a single crRNA: a high likelihood of viral escape, as the DNA repair mechanism NHEJ induces viral mutations that trigger viral escape.
- Combination of several viral targets: low escape possibilities
- Combinatorial approach by targeting both viral and host genes that encode important cofactors (e.g. CCR5), and addition of a gene encoding virus-neutralizing antibodies is even better.
Comparison of CRISPR-Cas editing platforms for gene therapy of HIV infections
CRISPR-Cas editing platforms (blue scissors) against HIV can be classified into three categories: the single targeting of HIV genes, the dual or multiplex targeting of HIV genes, and a combined targeting of HIV genes and host DNA to boost the activity restriction factors
- Carefully exclude off-target effects: the design of the crRNA should avoid the risk of unwanted large chromosomal deletions that can potentially lead to unwanted gene silencing, the removal of a tumor suppressor gene, or the activation of a proto-oncogene
- Delivery method: requires viral vectors e.g. Adenovirus or Lentivirus, but these vectors need to be targeting of reservoir cells (e.g. CD32a expression on reservoir T cells?)
- Immunogenicity of the CRISP-Cas proteins: this might imply need for immune suppressive therapy, which is of course not really wanted in an HIV patient.
I hope you enjoyed this part?
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