HIV, HIV Pathology and HIV Therapy - Ornelles, Beaty, Williamson Flashcards
- HIV-__ is more common and pathogenic than HIV-___ (doesn’t have vpu)
- HIV-1 is more common and pathogenic than HIV-2 (doesn’t have vpu)
Which HIV strain is more common, and more pathogenic? 1 or 2?
Which one expresses VPU, and what does VPU stand for/do?
HIV-1 is more pathogenic and more common. VPU stands for “viral protein unique.”
The Vpu protein acts in the degradation of CD4 in the endoplasmic reticulum and in the enhancement of virion release from the plasma membrane of infected cells.
Lentevirus is another class of ___
retroviruses
Does HIV have an envelope?
Yes. ENV gene encodes for gp120, a surface envelope protein. It protrudes outward and binds to the CD4 receptor on Th and macrophages.
___ is a critical protein for CD4 binding and HIV entry!
gp120, encoded by ENV gene.
Embedded within the gp120 protein envelope (encoded by __ gene), is the gp__, a ___ protein
Embedded within the gp120 protein envelope (encoded by ENV gene), is the gp41, a transmembrane protein
GAG gene encodes for the __, ___, __ and ___ within the HIV virion.
GAG gene encodes for the matrix, capsid, nucleocapsid and proteases within the HIV virion.
A defining characteristics between HIV and other retroviruses like lentevirus, is that HIV has ___, an important protein that regulates nuclear import of the HIV-1 pre-integration complex.
VPR, an important protein that regulates nuclear import of the HIV-1 pre-integration complex.
How does HIV replicate?
- HIV attaches and fuses with host cell after engaging in the host cell ___ chemokine receptor (on macrophages), or ___ chemokine receptor (on CD4+). This is done using gp___, which is encoded by the __ gene.
- reverse transcription occurs
- nuclear important of the ___ ___ complex
- non-enveloped genes are expressed
- envelope gene expression
- assemby and budding at ___ ___.
- post-budding maturation steps mediated by viral proteases
How does HIV replicate?
- HIV attaches and fuses with host cell after engaging in the host cell CCR5 chemokine receptor (on macrophages), or CXCR4 chemokine receptor (on CD4+). This is done using GP120, which is encoded by the ENV gene.
- reverse transcription occurs
- nuclear important of the PRE-INTEGRATION complex
- non-enveloped genes are expressed
- envelope gene expression
- assemby and budding at PLASMA MEMBRANE.
- post-budding maturation steps mediated by viral proteases
What gene encodes for reverse transcriptase and integrase?
Pol gene of HIV.
GAG gene encodes for: __, __, __, ___
Pol gene encodes for: __, ___
ENV gene encodes for: ___ ___
VPR gene encodes for: ____
GAG gene encodes for: matrix protein, capsid, nucleocapsid, protease
Pol gene encodes for: Rvs transcription, integrase
ENV gene encodes for: gp120, gp41
VPR gene encodes for: viral protein R
__ __ generates an extended DNA copy of the genome.
reverse transcriptase
CCR5 is a chemokine receptor on the ___, that is normally a receptor for ___, ___ and ___. It is favored ___ on. __% of transmission virus is CCR5 or macropage or M-tropic.
CXCR4 - chemokine receptor are normally for___ (__1). It is favored ___ on. CXCR4 viruses are ___ transmissible.
CCR5 is a chemokine receptor on the macrophage, that is normally a receptor for MIP1-beta, MIP1-alpha and RANTES. It is favored early on. 90% of transmission virus is CCR5 or macropage or M-tropic.
CXCR4 - chemokine receptor are normally forstromal derived factor (Sdf1). It is favored later on. CXCR4 viruses are less transmissible.
Reverse transcriptase generates an __ DNA copy of the genome. For HIV, it uses ___. The end result is a double stranded DNA product with ___ region on each side. This serves as the promoter and the poly-A tail for the virus. The duplicated DNA sequence generated at each end is termed ___. The product of cDNA and associated proteins is termed the __ ___ complex.
Reverse transcriptase generates an EXTENDED DNA copy of the genome. For HIV, it uses tRNA-3-Lys. The end result is a double stranded DNA product with LTR region on each side. This serves as the promoter and the poly-A tail for the virus. The duplicated DNA sequence generated at each end is termed THE LONG TERMINAL REPEAT (LTR). The product of cDNA and associated proteins is termed the PRE-INTEGRATION complex.
___ - associates with PIC (pre-integration complex) via gag proteins. __ binds directly to the nuclear pore and couples to it for protein import.
___ - couples PIC to nuclear protein import and may also bind nuclear pore proteins
___ - non-essential for nuclear import
VPR - associates with PIC (pre-integration complex) via gag proteins (MC NP - matrix, capsid, nucleocapsid, protease). It binds directly to the nuclear pore and couples to it for protein import.
Integrase - couples PIC to nuclear protein import and may also bind nuclear pore proteins
MA (matrix protein) - non-essential for nuclear import
During HIV viral genome integration,
___ binds nascent DNA. ___ binds to host DNA at a random site. The product is now called a ___ DNA.
During HIV viral genome integration,
Integrase binds nascent DNA. PIC (pro-integrase complex) binds to host DNA at a random site. The product is now called a pro-viral DNA.
___ binds nascent DNA and helps to integrate it into the host DNA.
Integrase
The integrated form of viral DNA is a __
provirus
What are the virion proteins in HIV?
What are the regulatory proteins?
What are the virion proteins in HIV?
Gag, pol, env, Vpr
VEPG
What are the regulatory proteins?
Tat, Rev, Vif, Vpu, Nef
Reverend Nef, tooted a viral fart and said vPU!
Two of the most essential regulatory proteins of HIV are: __ and ___.
What do they do?
TAT and REV
TAT makes viral transcription more efficient.
REV promotes the export of intron-bearing viral mRNA. REV binds the RRE present in the ENV gene sequence. REV couples RNA to protein export pathways. REV is equired for the expression of all forms of viral mRNA
First, HIV transcripts can be transcribed into __ and ___ mRNAs. Then, you need splicing events to generate ___, and the ___ proteins.
First, HIV transcripts can be transcribed into GAG and POL mRNAs. Then, you need splicing events to generate ENV, and the regulatory proteins.
Only properly ___ mRNAs acquire the proteins needed for transport into the cytoplasm for translation.
Only properly spliced mRNAs acquire the proteins needed for transport into the cytoplasm for translation.
The full length, singly spliced mRNAs have ___, which look like introns to the host cell. This prevents export of the transcripts. They multiply-spliced mRNA does not have an intron, so it can be demoved from the nucleus and get translated into proteins.
The multiply spliced mRNAs are __, __ and ___. After transclation, ___ then reenteres the nucleus, and binds to the ___ and __ the rate of transcription.
The full length, singly spliced mRNAs (ENV, VPR, VIF, VPU) have rev-response element (RRE), which look like introns to the host cell. This prevents export of the transcripts. The multiply-spliced mRNA does not have an intron, so it can be removed from the nucleus and get translated into proteins.
The multiply spliced mRNAs are TAT, REV and NEF. After translation, TAT then re-enters the nucleus, and binds to the (TAR - TAT response element) and INCREASES the rate of transcription.
GAG and POL precursor proteins are generated by unusual mechanisms. GAG and POL code for polyproteins that msut be ____ cleaved to generate anything active. Viral protease is encoded by __ gene. When the transcript is translated from the start codon to teh FIRST stop codon, __ gets generated. A frameshift past this first stop codon will generate ___
GAG and POL precursor proteins are generated by unusual mechanisms. GAG and POL code for polyproteins that msut be protealytically cleaved to generate anything active. Viral protease is encoded by GAG gene. When the transcript is translated from the start codon to the FIRST stop codon, GAG gets generated. A frameshift past this first stop codon will generate POL (which encodes for rvs transcriptase and integrase).
Lenteviruses express essential and non-essential accessory genes. __ and __ are essential
TAT and REV
HIV-1 has a stunning __ rate. HIV-1 RT introduces __ to __ mutations per proviral DNA genome. Approx. __ virus particles are made and destroyed per day in an untreated HIV patient. This is partially due to the fact that they infect __ T cells, which have a 1/2 life of 1.5 days.
Approx. ___ to ___ viral variants are generated per day. Each day, mutant swarms of viruses are generated in which each nucleotide has been changed. Empircal chances of drug resistant isolate is 1 in ___. This is why HIV is so hard to treat.
HIV-1 has a stunning mutation rate. HIV-1 RT introduces 1 to 10 mutations per proviral DNA genome. Approx. 10^9 virus particles are made and destroyed per day in an untreated HIV patient. This is partially due to the fact that they infect CD4 T cells, which have a 1/2 life of 1.5 days.
Approx. 10^4 to 10^5 viral HIV variants are generated per day. Each day, mutant swarms of viruses are generated in which each nucleotide has been changed. Empircal chances of drug resistant isolate is 1 in 10^4. This is why HIV is so hard to treat.
A statistical solution to HIV resistance is using ___ therapy.
____ - highly active anti-retroviral therapy is a 3 drug combo.
It reduces replication to undetectable levels.
A statistical solution to HIV resistance is using combination therapy.
HAART - highly active anti-retroviral therapy is a 3 drug combo.
It reduces replication to undetectable levels.
Initial reaction of HIV to host cell occurs at the __ surface. Then, HIV may interact with a __ or ___. The virus is then transported to regional __ __. The virus is introduced to a __ cell at a virological synapse. Local lymph tissue is heavily infeted by more distinct nodes, spleen, and circulating monocytes.
__ present antigens to T cells in __ __, activating T cells. Activated CD4 T cells become more receptive to ___, then non-activated T cells.
___ T cells require activated CD4 T cells. ___ are the most vulnurable to HIV.
___ redued surface levels of CD4 and MHC1 which helps the virus evade __.
Initial reaction of HIV to host cell occurs at the mucosal surface. Then, HIV may interact with a DC or macrophage. The virus is then transported to regional LNs. The virus is introduced to a T cell at a virological synapse. Local lymph tissue is heavily infeted by more distinct nodes, spleen, and circulating monocytes.
DC’s present antigens to T cells in LNs, activating T cells. Activated CD4 T cells become more receptive to HIV, then non-activated T cells.
CD8 T cells require activated CD4 T cells. CD4 T cells are the most vulnurable to HIV.
NEF reduces surface levels of CD4 and MHC1 which helps the virus evade death.
NEF reduces surface levels of __ and __ which helps the virus evade death.
NEF reduces surface levels of CD4 and MHC1 which helps the virus evade death.
What regulatory protein downregulates surface levels of MHC1 and CD4?
NEF –> allows the virus to evade killing
___, a viral HIV protein, blocks incorporation of anti-retroviral effector, APOBEC3G.
What does APOBEC3G do?
VIF
VIf blocks incorporation of anti-retro-effector, APOEBEC3G. APOEC3G is the host’s anti-retroviral effector. Basically, VIF is an anti-anti-retroviral.
What HIV viral protein blocks APOEBC3G?
VIF blocks APOEBC3G. APOEBC3G is good because it is an anti-retroviral. VIF, a viral protein encoded by HIV, is an anti-anti-retro-viral.
What is VPU?
Where is it found and what is its function?
VPU is viral protein unique. It is only found on HIV-1. It inactivates tetherin to promote virus release.
VPU is the difference between HIV-1 and HIV-2. VPU is why HIV-1 is so much more virulent.
Tetherin is an interferon-inducible host cell protein that prevents release of may viruses from the host cell surface. Remember, interferon upregulate antiviral defenses in non-infected cells. Tetherin is an example of an irterferon-induced protein. Viruses linked to tetherin traffic to lyosomes and die.
VPU is an HIV membrane protein that homehow inhibits tetherin.
VPU - inactivates ____. ___ is an interferon-induced host-cell protein that prevents what?
VPU - inactivates tetherin. Tetherin is an interferon-induced host-cell protein that prevents virus release from the membrane.
Match:
VIF
VPU
NEF
TAT
a. tetherin
b. APOEC3G
c. reduced levels of CD4 and MHC1
d. increase rate of transcription by binding to TAR
Match:
VIF - inhibits APOEBC3G (anti-anti retroviral)
VPU - inhibits tetherin
NEF - decreases surface expression of MHC-I and CD4, evading death of infected cell.
TAT - upregulated transcription of viral genome
Co-receptors change tropism during course of disease.
Primary receptor - CD4 on __ and __.
Secondary receptor: ___, a chemokine receptor on macrophages (normally used for MIP-1, and MIP-2 and RANTES).
Secondary receptor ___, a chemokine receptor on __ cells, which normally bind to ___. Viruses that evolve toward this receptor occurs in a ___ stage in the infection. Increased infection of ____ cells accelerates progression of AIDS.
Co-receptors change tropism during course of disease.
Primary receptor - CD4 on macrophage and Th cell.
Secondary receptor: CCR5, a chemokine receptor on macrophages (normally used for MIP-alpha, and MIP-beta and RANTES).
Secondary receptor CXCR4, a chemokine receptor on Th cells, which normally bind to Sdf-1. Viruses that evolve toward this receptor occurs in a later stage in the infection. Increased infection of CD4+ T cells accelerates progression of AIDS.
The viruses that utlizes ____ is the sexually transmitted virus.
CCR5
___ resonse to HIV determines the viral setpoint and cause of disease
CTL
The initial response to HIV will determine the viral ___ ____, which is a predictor of disease outcome.
Viral __ __ - the steady state level of viral RNA that you can detect in a patients blood
Busrt of ___ T cells in initial response starts killing virally infected cells, which unfortunately turns out to be __ cells.
Once __ levels drop below 200 cells/mm^3, you have ____
The initial response to HIV will determine the viral set point, which is a predictor of disease outcome.
Viral set point - the steady state level of viral RNA that you can detect in a patients blood
Busrt of CD8+ T cells in initial response starts killing virally infected cells, which unfortunately turns out to be CD4+ cells.
Once CD4+ T cells levels drop below 200 cells/mm^3, you have AIDS
HIV antiviral drugs target:
___ derivitaves and chemokine analogs (block attachment, fusion and entry)
___ analongs and non-___ inhibitos - blocks reverse transcriptase
__ inhbitors: blocks integration into host genome
TAT inhibitors: prevents transcription and post transcritional processing
Prevention of virion assembly and release - ___ inhibitors
HIV antiviral drugs target:
CD4 derivitaves and chemokine analogs (block attachment, fusion and entry)
nucleoside analongs and non-nucleoside inhibitos - blocks reverse transcriptase
Integrase inhbitors: blocks integration into host genome
TAT inhibitors: prevents transcription and post transcritional processing
Prevention of virion assembly and release - protease inhibitors
HAART interferes with retroviral replication but does not target, or have any effect on quiescent __ __ cells where proviral genome is already incorporated into the cell. Therefore, there is always a population of cells that can become active and re-establish significant viral loads when HAART therapy is withdrawm. Latent reservoirs can always be present.
HAART interferes with retroviral replication but does not target, or have any effect on quiescent CD4 T cells where proviral genome is already incorporated into the cell. Therefore, there is always a population of cells that can become active and re-establish significant viral loads when HAART therapy is withdrawm. Latent reservoirs can always be present.
VIF targets ____, the cytosine deaminase that hypermutates the viral genome.
APOEBC3G
VPU prevents __, an interferon-induced protein from directing budding HIV particles to lysosomes. VPU targets __ for degradation.
VPU prevents tetherin, an interferon-induced protein from directing budding HIV particles to lysosomes. VPU targets tetherin for degradation.
What is the mechanism of action of trimethoprim/sulfamethoxazole (TMP/SMX)?
Inhibits your tetrahydrofolic acid (THF).
In decreases THF availability and decreases thymidine synthesis and DNA synthesis in bacteria/fungus.
SMX completes with PABA to inhibit synthesis fo dihydrofolic acid, an intermediate step in the formation of THF. TMP binds to bacterial/fungal THF reductase (in preference to human dihydrofolate reductase), preventing the formation of THF.
In decreases THF availability and decreases thymidine synthesis and DNA synthesis in bacteria/fungus.
What are the three phases of HIV?
- Acute phase - characterized by a high level of virus production and viremia; symptoms are non specific
- Chronic phase - a smoldering, low level HIV replication, predominantly in lymphoid tissue, which may last several years
- Crisis phase - breakdown of host defenses, viral replication, and the symptoms of persisent fever, fatigue, weight loss and diarrhea.
Phases of HIV
- Acute phase - characterized by a high level of ___ production and viremia; symptoms are ___
- Chronic phase - a smoldering, __ ___ of HIV replication, predominantly in lymphoid tissue, which may last several years
- Crisis phase - breakdown of __ __, viral replication, and the symptoms of persisent fever, fatigue, weight loss and diarrhea.
- Acute phase - characterized by a high level of virus production and viremia; symptoms are non specific
- Chronic phase - a smoldering, low level HIV replication, predominantly in lymphoid tissue, which may last several years
- Crisis phase - breakdown of host defenses, viral replication, and the symptoms of persisent fever, fatigue, weight loss and diarrhea.
What is the significance of the CD4+ cell counts in an HIV patient?
HIV is stratified into three clinical categories based on ___ count.
- > or equal to ___ = low probability of progression
- 200-499
- <___ or rapidly falling = high probability of progression
HIV is stratified into three clinical categories based on CD4+
What is the significance of the CD4+ cell counts in an HIV patient?
HIV is stratified into three clinical categories based on CD4 count.
- > or equal to 500 = low probability of progression
- 200-499
- <200 or rapidly falling = high probability of progression
count.
How is the clinical pathoogy lab evaluation used to help diagnose HIV?
ELISA p24/HIV-1/2 antibody test
Western Blost - confirms the presence of HIV
PCR amplification for HIV-1
CD4+ counts
p24 antigen is tested for by ____.
ELISA
HIV testing:
- HIV __ ___
- ___ antigen
- ___ antibody
HIV testing:
- HIV viral load
- p24 antigen (ELISA)
- HIV antibody
What % of patients with AIDS have clinical evidence of neurologic dysfunction?
HIV can infect glial cells and macrophages in the brain.
30-50% have neurological disorders.
What is the cause of patient’s progressive confusion during the terminal phase of his illness?
- ___ diseases
- ____ diseases
- Primary HIV-associated syndromes
What is the cause of patient’s progressive confusion during the terminal phase of his illness?
- Opportunistic diseases
- Neoplastic diseases
- Primary HIV-associated syndromes
An HIV patient has macules, plaques, papules, and nodules on the skin. What virus was in infected by?
HHV-8 - Kaposi’s Sarcoma
What are the common opportunistic pathogens producing diarrhea in patients with AIDS?
Mycobacterial avium-intracellulare
Cryptosporidium or Isosporidium
CMV
How do CMV infections differ in immunocompetent person vs. immunosupressed person?
If you were to get CMV how would it present in you vs some who has N stage HIV?
In the immunocompetent patient, they would have a viral syndrome resembling acute infection mononucleosis.
In the immunosupressed patient, they will have disseminated, fulminant and lethal disese with multiorgan involvement.
HIV patient has ___ and ___.
Pneumocystis and CMV (below)
What virus is this?
JC virus
What virus is this?
Toxoplasma
EBV viral particles stain ___
black
Most patients with HIV will succumb to:
1.
2.
3.
Opportunisitic infections
Secondary neoplasms (Kaposi, lymphoma, cervical or anal cell carcinoma because HPV gets reactivated)
Neurological manifestations
Major capsid protein on HIV is p___
p24
Two major targets of HIV is the ___ and immune system
CNS and Immune System
HIV requries the __ cell to be activated before it replicated
CD4 T cell
Clinicopatholigic manifestations of infection divided into 3 phases:
1.
2.
3.
Acute viral syndrome - infection of memory CD4 T cells
Chronic phase - usually asymptomatic.
Clinical AIDS - breakdown of host defense
Many AIDS suffer from reactivation of __ infections. They also suffer from protozoal/helminthic infections like __ and ___.
Many AIDS suffer from reactivation of latent infections. They also suffer from protozoal/helminthic infections like toxoplasmosis and cryptosporidiosis.
___ ___ is the most common fungal infection in AIDS patients.
Pneumocystic jirovecii
- HIV-1 is more common and pathogenic than HIV-2 (doesn’t have vpu)
- Initial interaction with HIV by macrophages and DCs at mucosal surfaces which then travel to lymph nodes to present HIV to CD4+ T cellsà activated T cells more receptive to HIV infection, this, along with cell-to-cell presentation which avoids Ab recognition, contributes to HIV infection
- Attachment: HIV gp120:CD4 binding (T cells, macrophages) to attach and expose epitopes (conformational change)
- Fusion: HIV gp41:CCR5(early) or CXCR4(late) chemokine co-receptor binding, displays tropism during disease course
- RT in cytoplasm, followed by nuclear import of pre-integration complex: extended cDNA copy, virion protein R (Vpr, directly binds nuclear port-promotes entry unto nucleus of non-dividing cell unlike lentiviruses, IN and MA)
- Integration into random host DNA site followed by Gag & Pol expression, then Env
- Encodes essential replication protein Rev: regulates expression by promoting nuclear export of intron-bearing mRNA, binds Rev-response element
- Encodes essential replication protein Tat: transactivator, enhances ineffective transcription by increasing RNA pol II stability/processivity through recruitment of additional factors, binds TAR element of Env sequence (also required for all viral mRNA expression)
- Assembly and budding at PM and subsequent maturation by viral protease (immature-symmetrical, mature-trapezoidal)
- HIV-1 mutation rate of 1-10 per provirus x 10^9 virus particles/day in an untreated HIV pt = 10^4-5 variants/day
- HIV evades antiviral defenses through Nef (reduces surface levels of CD4 and MHC I), Vif (blocks antiviral effector APOBEC3G from hypermutating viral genome), and Vpu (inactivates tetherin to allow virion release in HIV-1 only)
- Poor humoral (Ab are ineffective d/t antigenic drift and epitope masking) and cell-mediated (T cells vigorous activity wanes, CD4 activation increases infectivity) immunity
- Viral set-point (steady state level of viral RNA in blood) determined by initial cellular response predicts disease course (higher is worse) and AIDS progression
- HIV non-progressors d/t MHC differences or CCR5 deletions incl. long-term/controllers (stable CD4, symptom free), elite controllers (undetectable viral load), viremic (stable CD4 w/ high viremia)
- HIV antiviral tx targeting unique HIV proteins requires 2 NRTIs (nucleoside analogs targeting RT) plus 1 other drug: NNRTI (non-nucleoside inhibitor targeting RT), integrase inhibitors, or protease inhibitors
- HAART approach with 3 drugs means 1 in 10^12 chance or 3 years until triple-resistant mutant arises
- Plasma HIV RNA changes w/ HAART have steep decline in phase 1 (decrease in CD4, short-lived cells), slow decline in phase 2 (decrease in macrophages, long-lived cells), and steady plateau in phase 3 (latent CD4 memory cells, below detection)
- Development of a vaccine is hard d/t rapid mutation (“Ag drift”), only 4 identified epitopes for Ab binding (on Env proteins), and a highly glycosylated envelope proteins (gp120)
- HIV-1 is more common and pathogenic than HIV-2 (doesn’t have vpu)
- Initial interaction with HIV by macrophages and DCs at mucosal surfaces which then travel to lymph nodes to present HIV to CD4+ T cellsà activated T cells more receptive to HIV infection, this, along with cell-to-cell presentation which avoids Ab recognition, contributes to HIV infection
- Attachment: HIV gp120:CD4 binding (T cells, macrophages) to attach and expose epitopes (conformational change)
- Fusion: HIV gp41:CCR5(early) or CXCR4(late) chemokine co-receptor binding, displays tropism during disease course
- RT in cytoplasm, followed by nuclear import of pre-integration complex: extended cDNA copy, virion protein R (Vpr, directly binds nuclear port-promotes entry unto nucleus of non-dividing cell unlike lentiviruses, IN and MA)
- Integration into random host DNA site followed by Gag & Pol expression, then Env
- Encodes essential replication protein Rev: regulates expression by promoting nuclear export of intron-bearing mRNA, binds Rev-response element
- Encodes essential replication protein Tat: transactivator, enhances ineffective transcription by increasing RNA pol II stability/processivity through recruitment of additional factors, binds TAR element of Env sequence (also required for all viral mRNA expression)
- Assembly and budding at PM and subsequent maturation by viral protease (immature-symmetrical, mature-trapezoidal)
- HIV-1 mutation rate of 1-10 per provirus x 10^9 virus particles/day in an untreated HIV pt = 10^4-5 variants/day
- HIV evades antiviral defenses through Nef (reduces surface levels of CD4 and MHC I), Vif (blocks antiviral effector APOBEC3G from hypermutating viral genome), and Vpu (inactivates tetherin to allow virion release in HIV-1 only)
- Poor humoral (Ab are ineffective d/t antigenic drift and epitope masking) and cell-mediated (T cells vigorous activity wanes, CD4 activation increases infectivity) immunity
- Viral set-point (steady state level of viral RNA in blood) determined by initial cellular response predicts disease course (higher is worse) and AIDS progression
- HIV non-progressors d/t MHC differences or CCR5 deletions incl. long-term/controllers (stable CD4, symptom free), elite controllers (undetectable viral load), viremic (stable CD4 w/ high viremia)
- HIV antiviral tx targeting unique HIV proteins requires 2 NRTIs (nucleoside analogs targeting RT) plus 1 other drug: NNRTI (non-nucleoside inhibitor targeting RT), integrase inhibitors, or protease inhibitors
- HAART approach with 3 drugs means 1 in 10^12 chance or 3 years until triple-resistant mutant arises
- Plasma HIV RNA changes w/ HAART have steep decline in phase 1 (decrease in CD4, short-lived cells), slow decline in phase 2 (decrease in macrophages, long-lived cells), and steady plateau in phase 3 (latent CD4 memory cells, below detection)
- Development of a vaccine is hard d/t rapid mutation (“Ag drift”), only 4 identified epitopes for Ab binding (on Env proteins), and a highly glycosylated envelope proteins (gp120)
