One World, One Hope——What Can We Do about AIDS?

4.1 The Morphological Structure of HIV

The human immunodeficiency virus is approximately 120 nanometers in diameter and is generally spherical. It mainly includes the viral envelope, and the protein gp120 and gp41 (transmembrane protein). Inward is a spherical matrix formed of protein p17, and a semi-conical capsid formed by protein p24. The capsid contains viral RNA genomes, enzymes (reverse transcriptase, integrase, protease), and other components from host cells (such as tRNAlys3, which acts as a primer for reverse transcription).

Figure 5 The structure of HIV

4.2 HIV Genomes

The viral genome is two identical positive strand RNAs, each of which is about 9.2 -9.8 kb. Both ends are long terminal repeats (LTR), containing cis-regulated sequences that control the expression of provirus. It has been demonstrated that LTR has promoters and enhancers and contains negative regulatory regions. The sequences between LTR encode at least nine proteins, which can be divided into three types: structural proteins, regulatory proteins and auxiliary proteins.

Structural Protein

• The gag gene can encode polymeric precursor protein, which is hydrolyzed by protease to form P17 and P24 nucleoprotein.
• The Pol gene encodes a polymerase precursor protein that is cleaved to form proteases, integrase, reverse transcriptase, and ribonuclease, all of which are required for viral proliferation ^[9].
• The env gene encodes a precursor protein and is glycosylated to gp160, gp120 and gp41.

Regulatory Protein

• The protein encoded by the TaT gene can bind to LTR to increase viral transcription rate.
• The Rev gene encodes a cis-activator that can act on the cis-acting suppression sequences (Crs) in env and gag to enhance the expression of gag and env genes.

Accessory Regulatory Proteins

• The Nef gene encodes the protein P27, which negatively regulates the expression of the HIV gene.
• The Vif gene may affect free HIV infectivity, virion production, and in vivo transmission.
• The VPU gene is unique to HIV-1 and is essential for efficient replication of HIV and assembly and maturation of virions.
• The protein encoded by the Vpr gene is a weak transcriptional activator that plays a role in the reproductive cycle in vivo.

Compared with HIV-1, the HIV-2 gene does not contain the VPU gene, but has an unexplained VPX gene.

5.1 Source of Infection

HIV-infected persons are the source of infection. HIV has been isolated from blood, semen, vaginal secretions, milk, etc.

The ability of HIV to survive in vitro is extremely poor, it is not resistant to high temperatures. So shaking hands, hugging, kissing, swimming, mosquito bites, sharing cutlery, coughing or sneezing, daily contact, etc. will not spread.

5.2 HIV Transmission

The following are the three main modes of communication ^[10]:

Sexual Transmission

HIV is present in the semen and vaginal secretions of infected people. Sexual behavior can easily cause minor skin mucosa damage, and the virus can be infected through the damaged area into the blood.

Blood Transmission

The human body is exposed to blood or blood products containing HIV, intravenous drug use, and transplant tissues and organs of infected patients are at risk of contracting AIDS.

Mother-to-Child Transmission

Women infected with HIV can pass the virus to the fetus during pregnancy and childbirth. The infected woman can also pass the virus to the child who is breastfeeding through breastfeeding.

Figure 6 Transmission of AIDS

Figure 7 No HIV transmission

5.3 Pathogenic Mechanism

It is well known that AIDS is an Immunodeficiency disease caused by the Human Immunodeficiency Virus (HIV). HIV selectively invades CD4 molecules, mainly T4 lymphocytes, monocyte macrophages, dendritic cells, and the like.

Pathogenic Process

The CD4 molecule on the cell surface is the HIV receptor. After the HIV membrane protein gp120 binds to the CD4 on the cell membrane. The conformation of gp120 changes, causing gp41 to be exposed. Meanwhile, gp120-CD4 binds to the chemokines CXCR4 or CXCR5 on the surface of the target cells to form the cd4-gp120-cxcr4 /CXCR5 tri-molecular complex. Gp41 uses its hydrophobic properties to mediate the fusion of viral cysts and cell membranes. Eventually the cells are destroyed. Over time, HIV destroys so many of these cells that the body cannot fight infection and disease, making people more susceptible to other infections or infection-related cancers.

5.4 The Stage of HIV Infection

The three stages of HIV infection are: Acute HIV Infection Stage; Clinical Latency Stage; AIDS (Acquired Immunodeficiency Syndrome).

Acute HIV Infection Stage

Many (but not all) people develop flu-like symptoms within 2 to 4 weeks of infection. HIV symptoms include fever, gland swelling, sore throat, AIDS rash, muscle and joint pain, and headache in this stage.

Clinical Latency Stage

The incubation period refers to the period in which the virus survives or develops in the human body without causing symptoms. During the clinical latency stage, standard laboratory tests fail to detect the virus. But people in this period can still transmit HIV to others. The average clinical latency stage was 10 years.

AIDS (Acquired Immunodeficiency Syndrome)

AIDS is the most severe stage of HIV infection. The immune system of AIDS patients is seriously damaged, and they will suffer from more and more serious diseases, called opportunistic infections. When your CD4 cell count is less than 200 cells per cubic millimeter of blood (200 cells/mm³), you are considered to have developed AIDS. (In populations with a healthy immune system, the number of CD4 cells is between 500 and 1600/mm³).

6.1 HIV-Associated Dementia

Primary HIV-related nervous system diseases include Peripheral neuropathy, myelopathy and HIV encephalopathy. As these diseases are related to clinical dementia, they are called AIDS dementia complex (ADC). HIV-associated dementia (HAD) often has low memory, inattention, unresponsiveness, and time and space orientation disorders as initial symptoms, and the disease progresses progressively. Patients with advanced HAD can develop severe dementia ^[11].

6.2 Wasting Syndrome

HIV wasting syndrome showed a significant decrease in body weight (> 10%) and chronic diarrhea or weakness. Intermittent or persistent fever is also one of the basis for HIV diagnosis.

6.3 AIDS nephropathy

Kidney damage caused by HIV includes thrombotic microangiopathy caused directly by HIV, and immune-mediated glomerulonephritis and nephropathy. HIV-induced kidney disease was first reported by American scholar Rao in 1984 and officially named HIV associated Nephropathy (HIVAN). Renal biopsy is the primary means of confirming HIVA.

7.1 Antibody Detection

HIV antibodies in serum are an indirect indicator of HIV infection. The widely used methods of AIDS test are the fourth generation test, enzyme-linked immunosorbant assay and chemiluminescent immunoassay. The window period of AIDS can be shortened to 14 ~ 21 days ^[13]. Although HIV antibodies were not detected during the window period, they were contagious. Other test methods include: particle agglutination reagent, Dot-blot assay (a rapid ELISA method.)

7.2 Antigen Detection

Pathogen detection mainly refers to direct detection of virus or viral genes from host samples by virus isolation and culture, electron microscopic observation, viral antigen detection and gene assay. For clinical diagnosis, antigen detection and RT-PCR (reverse transcription-PCR) are generally used.

7.3 Nucleic Acid Detection

HIV nucleic acid test can be used for the auxiliary diagnosis, course monitoring, treatment program guidance, determination of curative effect and prediction of disease progression, etc.

Commonly used methods for detecting HIV viral load include reverse transcription PCR (RT-PCR), nucleic acid sequence based amplification (NASBA), branched DNA hybridization (bDNA), real-time fluorescence quantitative PCR.

8.1 AIDS Prevention

If you are HIV-negative, you have several options to protect yourself from HIV infection. The more you take these actions, the safer you will be.

• Use condoms.
• Reduce your number of sexual partners.
• Pre-exposure prophylaxis. It refers to high-risk groups taking HIV drugs daily to reduce the risk of infection. The federal guidelines recommend that consideration should be given to those who are HIV- and have a continuing sexual relationship with HIV positive partners.
• Post-exposure prophylaxis (PEP) means taking antiretroviral drugs to prevent infection after possible exposure to HIV. PEP should only be used in emergencies and must be used within 72 hours of the most recent possible exposure to HIV.

If you are HIV+, you can take many steps to prevent HIV transmission to HIV-negative partners.

• Use AIDS drugs to prevent sexual transmission of HIV, this is called treatment as prevention (TasP).This is one of the most effective options for preventing HIV transmission.
• If HIV carriers can take HIV drugs throughout pregnancy, childbirth and childbirth, the risk of mother-to-child transmission during pregnancy, childbirth and childbirth can be reduced.
• Choose a less risky sexual behavior
• Strengthen public HIV education and understanding of government HIV/AIDS policies.

8.2 The Life Cycle of HIV

• The virions bind to host cell surface receptors and penetrate the cell membrane.
• The virion remove the protein shell in the cytoplasm of target cells, and release the gene RNA and reverse transcriptase (RT).
• Viral RNA is reverse transcribed into proviral DNA under the catalysis of reverse transcriptase.
• The proviral DNA binds to the virally encoded integrase (IN), forms a preinteg ration complex (PIC), and is translocated into the nucleus.
• Viral DNA is integrated into the chromosome of the host cell by the integrase in the nucleus. Studies on the complete sequencing of the human genome have shown that HIV is preferentially integrated into actively transcribed genes ^[14], and this feature may further enable them to be copied and transmitted.
• Replication and translation are conducted by using the existing gene replication and protein expression system of host cells.
• The protease (PR) of the virus cleaves the polyprotein produced by gene expression into various active structural and functional proteins, and assembles with the replicated genetic material RNA into a mature progeny virus.
• Once all of the viral components are expressed, new virions assemble at the plasma membrane and bud from the cell surface. To achieve complete budding, the virus hijacks components of the cell's vesicular transport machinery.

Figure 8 Life cycle of HIV and targets of anti-HIV drug

8.3 Anti-aids Drug Research

Based on the life cycle of HIV-1 as described above, the anti-aids drugs currently in use or under development mainly include:

• Entry inhibitor ^[15]: acts on HIV's viral attachment, coreceptor interaction, fusion of HIV and cells;
• Nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs): reverse transcription of viral RNA;
• Integrase inhibitor ^[16]: integration of proviral DNA;
• Protease inhibitors (PIs) ^[17]: transcription of DNA, translation of viral proteins, viral assembly, budding and maturation of HIV Virion ^{[18] [19]}.

At present, the world's hottest and most successful new anti-aids drugs with new mechanism of action mainly focus on the two fields of HIV-1 entry inhibitor and HIV-1 integrase inhibitor ^[20]. This new anti-AIDS drug has brought new therapeutic hopes to more and more drug-resistant patients ^[21].

In May 2018, a research team used CRISPR/Cas9 editing technology to develop an effective method to destroy the regulatory genes of HIV and successfully inhibit the proliferation of HIV-1 in infected cells ^[22].

Potential Future Options

There are currently no HIV vaccine to prevent or treat HIV infection. However, scientists are working hard to develop. Currently, a vaccine trial called HVTN702, supported by the National Institutes of Health, is testing whether an experimental vaccine program can safely prevent HIV infection among adults in South Africa.