HIV, HIV Pathology and HIV Therapy - Ornelles, Beaty, Williamson

Question 1

• HIV-__ is more common and pathogenic than HIV-___ (doesn’t have vpu)

Answer 1

• HIV-1 is more common and pathogenic than HIV-2 (doesn’t have vpu)

Question 2

Which HIV strain is more common, and more pathogenic? 1 or 2?

Which one expresses VPU, and what does VPU stand for/do?

Answer 2

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.

Question 3

Lentevirus is another class of ___

Answer 3

retroviruses

Question 4

Does HIV have an envelope?

Answer 4

Yes. ENV gene encodes for gp120, a surface envelope protein. It protrudes outward and binds to the CD4 receptor on Th and macrophages.

Question 5

___ is a critical protein for CD4 binding and HIV entry!

Answer 5

gp120, encoded by ENV gene.

Question 6

Embedded within the gp120 protein envelope (encoded by __ gene), is the gp__, a ___ protein

Answer 6

Embedded within the gp120 protein envelope (encoded by ENV gene), is the gp41, a transmembrane protein

Question 7

GAG gene encodes for the __, ___, __ and ___ within the HIV virion.

Answer 7

GAG gene encodes for the matrix, capsid, nucleocapsid and proteases within the HIV virion.

Question 8

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.

Answer 8

VPR, an important protein that regulates nuclear import of the HIV-1 pre-integration complex.

Question 9

How does HIV replicate?

1. 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.
2. reverse transcription occurs
3. nuclear important of the ___ ___ complex
4. non-enveloped genes are expressed
5. envelope gene expression
6. assemby and budding at ___ ___.
7. post-budding maturation steps mediated by viral proteases

Answer 9

How does HIV replicate?

1. 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.
2. reverse transcription occurs
3. nuclear important of the PRE-INTEGRATION complex
4. non-enveloped genes are expressed
5. envelope gene expression
6. assemby and budding at PLASMA MEMBRANE.
7. post-budding maturation steps mediated by viral proteases

Question 10

What gene encodes for reverse transcriptase and integrase?

Answer 10

Pol gene of HIV.

Question 11

GAG gene encodes for: __, __, __, ___

Pol gene encodes for: __, ___

ENV gene encodes for: ___ ___

VPR gene encodes for: ____

Answer 11

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

Question 12

__ __ generates an extended DNA copy of the genome.

Answer 12

reverse transcriptase

Question 13

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.

Answer 13

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.

Question 14

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.

Answer 14

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.

Question 15

___ - 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

Answer 15

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

Question 16

During HIV viral genome integration,

___ binds nascent DNA. ___ binds to host DNA at a random site. The product is now called a ___ DNA.

Answer 16

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.

Question 17

___ binds nascent DNA and helps to integrate it into the host DNA.

Answer 17

Integrase

Question 18

The integrated form of viral DNA is a __

Answer 18

provirus

Question 19

What are the virion proteins in HIV?

What are the regulatory proteins?

Answer 19

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!

Question 20

Two of the most essential regulatory proteins of HIV are: __ and ___.

What do they do?

Answer 20

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

Question 21

First, HIV transcripts can be transcribed into __ and ___ mRNAs. Then, you need splicing events to generate ___, and the ___ proteins.

Answer 21

First, HIV transcripts can be transcribed into GAG and POL mRNAs. Then, you need splicing events to generate ENV, and the regulatory proteins.

Question 22

Only properly ___ mRNAs acquire the proteins needed for transport into the cytoplasm for translation.

Answer 22

Only properly spliced mRNAs acquire the proteins needed for transport into the cytoplasm for translation.

Question 23

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.

Answer 23

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.

Question 24

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 ___

Answer 24

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).

Question 25

Lenteviruses express essential and non-essential accessory genes. __ and __ are essential

Answer 25

TAT and REV

Question 26

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.

Answer 26

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.

Question 27

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.

Answer 27

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.

Question 28

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 __.

Answer 28

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.

Question 29

NEF reduces surface levels of __ and __ which helps the virus evade death.

Answer 29

NEF reduces surface levels of CD4 and MHC1 which helps the virus evade death.

Question 30

What regulatory protein downregulates surface levels of MHC1 and CD4?

Answer 30

NEF –> allows the virus to evade killing

Question 31

___, a viral HIV protein, blocks incorporation of anti-retroviral effector, APOBEC3G.

What does APOBEC3G do?

Answer 31

VIF

VIf blocks incorporation of anti-retro-effector, APOEBEC3G. APOEC3G is the host’s anti-retroviral effector. Basically, VIF is an anti-anti-retroviral.

Question 32

What HIV viral protein blocks APOEBC3G?

Answer 32

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.

Question 33

What is VPU?

Where is it found and what is its function?

Answer 33

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.

Question 34

VPU - inactivates ____. ___ is an interferon-induced host-cell protein that prevents what?

Answer 34

VPU - inactivates tetherin. Tetherin is an interferon-induced host-cell protein that prevents virus release from the membrane.

Question 35

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

Answer 35

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

Question 36

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.

Answer 36

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.

Question 37

The viruses that utlizes ____ is the sexually transmitted virus.

Answer 37

CCR5

Question 38

___ resonse to HIV determines the viral setpoint and cause of disease

Answer 38

CTL

Question 39

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 ____

Answer 39

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

Question 40

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

Answer 40

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

Question 41

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.

Answer 41

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.

Question 42

VIF targets ____, the cytosine deaminase that hypermutates the viral genome.

Answer 42

APOEBC3G

Question 43

VPU prevents __, an interferon-induced protein from directing budding HIV particles to lysosomes. VPU targets __ for degradation.

Answer 43

VPU prevents tetherin, an interferon-induced protein from directing budding HIV particles to lysosomes. VPU targets tetherin for degradation.

Question 44

What is the mechanism of action of trimethoprim/sulfamethoxazole (TMP/SMX)?

Answer 44

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.

Question 45

What are the three phases of HIV?

Answer 45

1. Acute phase - characterized by a high level of virus production and viremia; symptoms are non specific
2. Chronic phase - a smoldering, low level HIV replication, predominantly in lymphoid tissue, which may last several years
3. Crisis phase - breakdown of host defenses, viral replication, and the symptoms of persisent fever, fatigue, weight loss and diarrhea.

Question 46

Phases of HIV

1. Acute phase - characterized by a high level of ___ production and viremia; symptoms are ___
2. Chronic phase - a smoldering, __ ___ of HIV replication, predominantly in lymphoid tissue, which may last several years
3. Crisis phase - breakdown of __ __, viral replication, and the symptoms of persisent fever, fatigue, weight loss and diarrhea.

Answer 46

1. Acute phase - characterized by a high level of virus production and viremia; symptoms are non specific
2. Chronic phase - a smoldering, low level HIV replication, predominantly in lymphoid tissue, which may last several years
3. Crisis phase - breakdown of host defenses, viral replication, and the symptoms of persisent fever, fatigue, weight loss and diarrhea.

Question 47

What is the significance of the CD4+ cell counts in an HIV patient?

HIV is stratified into three clinical categories based on ___ count.

1. > or equal to ___ = low probability of progression
2. 200-499
3. <___ or rapidly falling = high probability of progression

Answer 47

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.

1. > or equal to 500 = low probability of progression
2. 200-499
3. <200 or rapidly falling = high probability of progression

count.

Question 48

How is the clinical pathoogy lab evaluation used to help diagnose HIV?

Answer 48

ELISA p24/HIV-1/2 antibody test

Western Blost - confirms the presence of HIV

PCR amplification for HIV-1

CD4+ counts

Question 49

p24 antigen is tested for by ____.

Answer 49

ELISA

Question 50

HIV testing:

1. HIV __ ___
2. ___ antigen
3. ___ antibody

Answer 50

HIV testing:

1. HIV viral load
2. p24 antigen (ELISA)
3. HIV antibody

Question 51

What % of patients with AIDS have clinical evidence of neurologic dysfunction?

Answer 51

HIV can infect glial cells and macrophages in the brain.

30-50% have neurological disorders.

Question 52

What is the cause of patient’s progressive confusion during the terminal phase of his illness?

1. ___ diseases
2. ____ diseases
3. Primary HIV-associated syndromes

Answer 52

What is the cause of patient’s progressive confusion during the terminal phase of his illness?

1. Opportunistic diseases
2. Neoplastic diseases
3. Primary HIV-associated syndromes

Question 53

An HIV patient has macules, plaques, papules, and nodules on the skin. What virus was in infected by?

Answer 53

HHV-8 - Kaposi’s Sarcoma

Question 54

What are the common opportunistic pathogens producing diarrhea in patients with AIDS?

Answer 54

Mycobacterial avium-intracellulare

Cryptosporidium or Isosporidium

CMV

Question 55

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?

Answer 55

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.

Question 56

HIV patient has ___ and ___.

Answer 56

Pneumocystis and CMV (below)

Question 57

What virus is this?

Answer 57

JC virus

Question 58

What virus is this?

Answer 58

Toxoplasma

Question 59

EBV viral particles stain ___

Answer 59

black

Question 60

Most patients with HIV will succumb to:

1.

2.

3.

Answer 60

Opportunisitic infections

Secondary neoplasms (Kaposi, lymphoma, cervical or anal cell carcinoma because HPV gets reactivated)

Neurological manifestations

Question 61

Major capsid protein on HIV is p___

Answer 61

p24

Question 62

Two major targets of HIV is the ___ and immune system

Answer 62

CNS and Immune System

Question 63

HIV requries the __ cell to be activated before it replicated

Answer 63

CD4 T cell

Question 64

Clinicopatholigic manifestations of infection divided into 3 phases:

1.

2.

3.

Answer 64

Acute viral syndrome - infection of memory CD4 T cells

Chronic phase - usually asymptomatic.

Clinical AIDS - breakdown of host defense

Question 65

Many AIDS suffer from reactivation of __ infections. They also suffer from protozoal/helminthic infections like __ and ___.

Answer 65

Many AIDS suffer from reactivation of latent infections. They also suffer from protozoal/helminthic infections like toxoplasmosis and cryptosporidiosis.

Question 66

___ ___ is the most common fungal infection in AIDS patients.

Answer 66

Pneumocystic jirovecii

Question 67

• 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)

Answer 67

• 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)