T12 HIV-AIDS

retrovirus - baltimore classification

class VI

reverse transcriptase

convert ssRNA+ → cDNA

retrovirus - replication

reverse transcriptase convert ssRNA+ → cDNA → inject into host chromosome → accompanied by host cell transcription

retrovirus - gene products

gag, pol, env 

gag - codes for

structural proteins → capsid & matrix

pol - codes for

reverse transcriptase / RdDp, protease, integrase 

protease - for what

viral maturation

integrase - for what

integrate viral DNA to host chromosome

env - codes for

spike → transmembrane protein & surface protein

HIV - family

retrovirus

HIV - genus

lentivirus

lentivirus - genetic material

ssRNA+

lentivirus - structure

rod-shaped core

lentivirus - genome

diploid (2 copies)

lentivirus - replication location

nucleus

after reverse transcription

viral DNA integrates genome into host’s chromosomes by integrase → “proviral” state → can stay latent & reactivate later 

maturation phase

bud from plasma membrane by protease

tropism

depends on whether host cell has specific receptors to virus or not 

lentivirus - infect what

CD4+ & macrophages

gag - matrix (MA)

p17

gag - capsid (CA)

p24

gag - nucleocapsid (NC)

p9

pol - protease (PR)

p11

pol - reverse transcriptase (RT)

p66, p51

pol - integrase (IN)

p32

env - surface protein (SU)

gp120

env - transmembrane protein (TM)

gp41

HIV-1 - accessory gene

VPU

HIV-2 - accessory gene

VPX

regulatory proteins

tat & rev

tat

enhance efficacy of transcription

rev

assist nuclear export

accessory proteins

nef, vif,vpr, vpu, vpx

nef

downregulate MHC I & II → T cell cannot activate 

vif

inhibit APOBEC deaminase

APOBEC deaminase inhibition

host cell cannot degrade virus nucleic acid → HIV can replicate inside host → proviral state

vpr

transport pre-integration complex to nucleus & arrest cell cycle in G2

vpu

promotes degradation of CD4 → enhance virus release out of host by budding

vpx

transport pre-integration complex to nucleus & induce degradation of SAMHD1

degradation of SAMHD1

cannot control dNTP → promote HIV replication

HIV-1 - where

ward / hospitals (main infection)

HIV-2 - where

africa

HIV-1 - groups

M N O

HIV-2 - groups

A B C D E F

HIV that infect macrophage

M-tropic / R5-tropic

HIV coreceptor on macrophage 

CCR5

HIV that infect lymphocyte

T-tropic / X4-tropic

HIV coreceptor on lymphocyte

CXCR4

HIV that infect both macrophage & lymphocytes

dual-tropic

HIV coreceptor on dual-tropic

CCR5 + CXCR4

subtypes arise due to what

high mutation rates from lack of proofreading in reverse transcriptase

lack of proofreading results in…

HIV genetically diverse → evolve in quasi species

HIV replication - first step

GP120 of virus + CD4 of host cell → conformational change

HIV replication - after first conformational change

GP41 appears → bind to coreceptor → conformation change

HIV replication - after second conformational change

virus fuse envelope with plasma membrane (fusion mechanism)

HIV replication - after fusion

nucleocapsid released into cytoplasm along with ssRNA+

HIV replication - after ssRNA+ released into cytoplasm

reverse transcriptase / RdDp convert their genome into cDNA

HIV replication - after cDNA form

integrase attach to viral DNA → transfer viral DNA to host’s nucleus → cleave host’s chromosomes → integrate viral DNA into host chromosome → “proviral” state

HIV replication - after proviral state 

accompanied by host cell’s replication 

HIV replication - after host cell replication, produce…

ssRNA+ (genome for new virions) & mRNA (produce viral proteins)

HIV replication - viral proteins production

translate to polyproteins → assemlby → bud from host cell → “immature” → protease cleave → active proteins “mature” → can infect other cells

HIV pathogenesis - first step

virus spread to bloodstream

HIV pathogenesis - after in bloodstream

virus first infect macrophage → carry HIV to lymph nodes → infect more CD4+ T cells → multiples & spread systemically through bloodstream

HIV pathogenesis - latency

HIV replicates slowly → virus hide inside infected CD4+ & macrophages as provirus

HIV pathogenesis - macrophage as virus reservoir

keeps HIV alive (even when CD4+ die) → transport virus to various organs

HIV pathogenesis - macrophages in different organs

microgial cells (AIDS dementia), alveolar macrophage (pulmonary infection), dendritic cells (vehicle to spread HIV to T cells)

HIV pathogenesis - when viral replication increase

HIV kills CD4+ → cell cytolysis → drop in CD4+ → immune system collapse 

HIV pathogenesis - immunological consequences 

immunodeficiency, loss of B cell control, loss of DTH, loss of T cell function

HIV pathogenesis - immunodeficiency

reduced immune response → vulnerable to infections

HIV pathogenesis - loss of B cell control

lymphadenopathy & hypergammaglobulinemia (increased antibodies)

HIV pathogenesis - loss of DTH

poor macrophage activation → increased intracellular infections

HIV pathogenesis - loss of T cell function

inability to mount immune response → opportunistic infections 

T cells - permissive

lytic

T cells - nonpermissive

apoptosis

persistent phase - composed of

chronic & latent

chronic infection

virus still replicate

latent infection

virus don’t replicate 

course of untreated HIV infection

primary infection → dissemination to lymphoid organs → clinical latency / chronic infection → elevated HIV expression → AIDS → death

lead to death - how?

no treatment within 3 years

clinical latency - CD4+ & HIV levels

remain constant → fighting stage

clinical latency duration depends on…

host immunity status & genetics of host

macrophage escape latency how

reactivation by cytokines

macrophage after reactivated

act as vehicle to carry virus to other tissues → transport to brain 

cytokines from macrophage

activate T cells from latency & autocrine to activate itself 

T cells after latency 

decreased function → destroyed by lysis / apoptosis → immunocompromised stage / AIDS

HIV - stages

stage 1 (acute HIV infection), stage 2 (chronic HIV infection), stage 3 (AIDS)

stage 1 - clinical features

flu-like symptoms or asymptomatic

flu-like symptoms in stage 1

fever, chills, rash, night sweats, muscle aches, sore throat, fatigue, swollen lymph nodes, mouth ulcers 

stage 1 - tests

antigen/antibody test or nucleic acid test (NAATs)

stage 2 - clinical features

asymptomatic / clinical latency → virus active but reproduce at very low levels 

stage 2 - can transmit?

yes

stage 2 - HIV & CD4 levels

viral load increase & CD4 decrease

stage 2 - how to not progress further

take HIV medicine as prescribed

stage 3 - clinical features

opportunistic infections → die in 3 years if no treatment

stage 3 - CD4 cell count

< 200

stage 1 - CD4 cell count

>= 500

stage 2 - CD4 cell count

200-499

AIDS - what is it

pronounced suppression of immune system & development of wide variety of severe opportunistic infections

AIDS - prodrome symptoms

diarrhea, fatigue, malaise, weight loss, fever, shortness of breath, chronic diarrhea, hairy leukoplakia, oral candidiasis, lymphadenopathy, memory loss, depression, neurologic disorders

hairy leukoplakia & oral candidiasis - symptoms

white patches on tongue