HIV Pathogenesis and Immunity Flashcards
CXCR4 predominantly expressed on [] cells.
CXCR4 predominantly expressed on naïve CD4 T cells.
CCR5 predominantly expressed on [] cells.
CCR5 predominantly expressed on memory CD4 T cells, macrophages, monocytes, Langerhans cells of skin, perivascular macrophages, microglial cells.
The first cells to be infected with HIV are [].
The first cells to be infected with HIV are macrophages, Langerhans cells, mucosal T-cells – CD4+/CCR5+ cells.
- Infects efficiently and kills specifically the CD4+ T4 lymphocytes, initially mucosal T cells, characterized by loss of CD4+ T4 lymphocytes
- Can establish persistent infection characterized by the presence of replicating virus with little immunological abnormalities – clinical latency
- Antiretroviral therapy creates viral latency in many infected patients
[] acts on the LTR sequences known as TAR to increase the rate of viral transcription and may stabilize the RNAs.
Tat acts on the LTR sequences known as TAR to increase the rate of viral transcription and may stabilize the RNAs.
[] transports structural proteins mRNA from the nucleus to cytoplasm.
Rev transports structural proteins mRNA from the nucleus to cytoplasm.
- Rev binds to rev responsive element (RRE), located in the env gene.
- Rev may also be involved in splicing and stability of mRNAs
Nef
down regulates CD4+ expression, required for viral pathogenesis
Vif
increase virus infectivity
Vpr
Prevents cell proliferation, arrest cells in G2/M phase, upregulates virus expression
Vpu
Virus release and/or assembly
Vpx
in HIV 2 - Virus release and/or assembly
Genetic Variation in HIV
- HIV-1 possesses the most error-prone reverse transcriptase among all retroviruses
- Several variants or genotypes exist within an infected individual and clades and subtypes in infected population
- Clade M (major), O (outlier), N (new)
- M clade has A-H subtypes, B subtypes in the U.S.
- The variability is mainly in envelope region because of the immunologic pressure but also observed in other regions of the genome
- Results in change of cell tropism, replication level, virulence, immune escape
- Genetic variation causing problems in vaccine development
Pathogenesis of HIV
- Transmission of HIV (common route: sexual route)
- Acute phase of intense viral replication and dissemination to lymphoid tissues (acute-retroviral syndrome; flu or mono-like illness
- Activation of innate and adaptive immune response, unable to contain highly replicating/ mutating virus
- Persistent asymptomatic phase (clinical latency) of continued viral replication and immune activation
- Advanced phase of marked depletion of CD4 T lymphocytes (immune deficiency) leading to development of AIDS (opportunistic infections)
HIV Immune Response
- Early control by innate immunity and later adaptive to cause virus set point
- APCs present antigen to T cells to generate CD8+CTLs that kill HIV infected cells and control viremia, CTL escape mutants develop due mutation
- B cells respond to HIV antigens, collaborates with CD4 T cells to make neutralizing antibodies that also controls viremia, viral escape variants emerge
- Early in infection memory CD4+ T cells (mucosal) are depleted, but late in infection all CD4+ T cells are depleted causing immunodeficiency
HIV Immune Activation
Production of proinflammatory cytokines, TNF-a, IL-1, IL-6, IL-12, chemokines, IFN-a and LPS
Neutralizng Antibodies
HIV-1 gp120 and gp41 are the major target for humoral antibody response, the principal neutralizing domain (PND) is the variable 3 (V3) region, antibodies against most of HIV-1 proteins can be found in infected patients.
CD4+ T Cells Response
viral peptides presented by DC on MHC II to CD4 T cells, release of antiviral cytokines (INF-γ, TNF-α), help for antiviral antibody production
CD8+ T Cells Response
viral peptides presented by DC on MHC I to CD8 T cells, killing of virus infected cells, release of antiviral substances
Enhancing Antibodies
enhances HIV infection
Latency
- Clinical latency observed in HIV-1 infection that is long asymptomatic period following HIV infection
- Several factors can terminate clinical latency such as mutations, altered cell tropism, activation of infected T cells by mitogens and DNA viruses
- Patients treated with anti-retroviral therapy (ART) have significant decrease in viral load and increase in CD4 T cells count.
- Therefore, HIV becomes latent (low level to no viral replication) in resting T-lymphocytes, central memory T-lymphocytes, CD34 hematopoietic progenitor stem cells, and monocytes/ macrophages.
Immunodeficiency
CD4+ T cells depletion leads to generalized failure of cell mediated immunity resulting in opportunistic infection and malignancy
Depletion of HIV-1 infected CD4+ T cells
- No damage to the cells with very low or no virus
- Active virus production leads to cell death
- Humoral or cell mediated response may also lead to destruction of infected cell
- CD4+ cells surface expressing gp120 and gp41 can be killed by antibody-plus-complement lysis
- Cells expressing viral peptides with MHC I are killed by CTL response
- Lymph nodes contain 10 to 100 times more virus than circulating CD4+ T cells
Destruction of CD4+ T Cells
- In HIV infected individuals: normal to 50/ul
- In HIV infected patients, CD4+/CDB+ ratio is: 1.0 to 0.2 (normal CD4+/CD8+ ratio is 2.0)
- Opportunistic infections are based on CD4 counts
- Regeneration capacity of CD4 and CD8 cells is diminished in infected patients
Depletion of uninfected CD4+ T cells
- Syncytia formation and destruction by soluble gp120
- Interference with T-cell maturation
- Inappropriate programmed cell death
HIV Reservoirs
- GALT and Lymph Nodes
- Resting CD4+ T lymphocytes remain silently infected with HIV provirus
- The phenotype of these CD4+ T cells includes central memory CD4+ T cells (TCM), transitional memory CD4+ T cells (TTM) and effector memory CD4+ T cells (TEM)
Failure of the Immune System to Eliminate HIV Infection
- Cell-to-cell spread avoids virus recognition by antibodies
- High rate of mutation results in antigenic variation
- Virus escapes from antibody and CTL recognition
- Immune system unable to keep the pace with rapidly mutating virus
- Suppression of MHC I and II, interference with cytokine
- Establishing persistent infection
- Integration of viral genome into host chromosome
- Impaired T and B cell function, finally development of AIDS with opportunistic infections
